ID INSR_HUMAN Reviewed; 1382 AA. AC P06213; Q17RW0; Q59H98; Q9UCB7; Q9UCB8; Q9UCB9; DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot. DT 05-OCT-2010, sequence version 4. DT 27-MAR-2024, entry version 286. DE RecName: Full=Insulin receptor; DE Short=IR; DE EC=2.7.10.1; DE AltName: CD_antigen=CD220; DE Contains: DE RecName: Full=Insulin receptor subunit alpha; DE Contains: DE RecName: Full=Insulin receptor subunit beta; DE Flags: Precursor; GN Name=INSR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANTS GLY-2; HIS-171; RP THR-448 AND LYS-492. RX PubMed=2859121; DOI=10.1016/0092-8674(85)90334-4; RA Ebina Y., Ellis L., Jarnagin K., Edery M., Graf L., Clauser E., Ou J.-H., RA Masiarz F., Kan Y.W., Goldfine I.D., Roth R.A., Rutter W.J.; RT "The human insulin receptor cDNA: the structural basis for hormone- RT activated transmembrane signalling."; RL Cell 40:747-758(1985). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT), PROTEIN SEQUENCE OF 28-49 AND RP 763-782, GLYCOSYLATION AT ASN-43 AND ASN-769, AND VARIANT GLY-2. RX PubMed=2983222; DOI=10.1038/313756a0; RA Ullrich A., Bell J.R., Chen E.Y., Herrera R., Petruzzelli L.M., Dull T.J., RA Gray A., Coussens L., Liao Y.-C., Tsubokawa M., Mason A., Seeburg P.H., RA Grunfeld C., Rosen O.M., Ramachandran J.; RT "Human insulin receptor and its relationship to the tyrosine kinase family RT of oncogenes."; RL Nature 313:756-761(1985). RN [3] RP SEQUENCE REVISION TO 899-900. RA Chen E.Y.; RL Submitted (JUL-1985) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLY-2. RC TISSUE=Fetal liver; RX PubMed=2210055; DOI=10.2337/diacare.39.1.123; RA Seino S., Seino M., Bell G.I.; RT "Human insulin-receptor gene. Partial sequence and amplification of exons RT by polymerase chain reaction."; RL Diabetes 39:123-128(1990). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT), AND VARIANT GLY-2. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2. RX PubMed=3680248; DOI=10.1016/s0021-9258(18)47714-9; RA Araki E., Shimada F., Uzawa H., Mori M., Ebina Y.; RT "Characterization of the promoter region of the human insulin receptor RT gene. Evidence for promoter activity."; RL J. Biol. Chem. 262:16186-16191(1987). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2. RX PubMed=2806055; DOI=10.1016/0168-8227(89)90085-5; RA Araki E., Shimada F., Fukushima H., Mori M., Shichiri M., Ebina Y.; RT "Characterization of the promoter region of the human insulin receptor RT gene."; RL Diabetes Res. Clin. Pract. 7:S31-S33(1989). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2. RX PubMed=2777789; DOI=10.1016/s0021-9258(18)71612-8; RA Tewari D.S., Cook D.M., Taub R.; RT "Characterization of the promoter region and 3' end of the human insulin RT receptor gene."; RL J. Biol. Chem. 264:16238-16245(1989). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2. RC TISSUE=Skin fibroblast; RX PubMed=2280779; DOI=10.1210/mend-4-4-647; RA McKeon C., Moncada V., Pham T., Salvatore P., Kadowaki T., Accili D., RA Taylor S.I.; RT "Structural and functional analysis of the insulin receptor promoter."; RL Mol. Endocrinol. 4:647-656(1990). RN [11] RP PROTEIN SEQUENCE OF 28-44; 192-205; 299-314; 610-627 AND 763-780, ACTIVITY RP REGULATION, AND SUBUNIT. RC TISSUE=Placenta; RX PubMed=2211730; DOI=10.1016/s0021-9258(17)44805-8; RA Xu Q.-Y., Paxton R.J., Fujita-Yamaguchi Y.; RT "Substructural analysis of the insulin receptor by microsequence analyses RT of limited tryptic fragments isolated by sodium dodecyl sulfate- RT polyacrylamide gel electrophoresis in the absence or presence of RT dithiothreitol."; RL J. Biol. Chem. 265:18673-18681(1990). RN [12] RP PROTEIN SEQUENCE OF 28-45 AND 763-782, FUNCTION, AND FORMATION OF A HYBRID RP RECEPTOR WITH IGF1R. RC TISSUE=Placenta; RX PubMed=8257688; DOI=10.1021/bi00212a019; RA Kasuya J., Paz I.B., Maddux B.A., Goldfine I.D., Hefta S.A., RA Fujita-Yamaguchi Y.; RT "Characterization of human placental insulin-like growth factor-I/insulin RT hybrid receptors by protein microsequencing and purification."; RL Biochemistry 32:13531-13536(1993). RN [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 538-1382 (ISOFORM SHORT). RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [14] RP NUCLEOTIDE SEQUENCE [MRNA] OF 728-772 (ISOFORM LONG), AND ALTERNATIVE RP SPLICING. RX PubMed=2538124; DOI=10.1016/0006-291x(89)92439-x; RA Seino S., Bell G.I.; RT "Alternative splicing of human insulin receptor messenger RNA."; RL Biochem. Biophys. Res. Commun. 159:312-316(1989). RN [15] RP NUCLEOTIDE SEQUENCE [MRNA] OF 744-823 (ISOFORM LONG), TISSUE SPECIFICITY, RP LIGAND-BINDING, AND AUTOPHOSPHORYLATION. RX PubMed=2369896; DOI=10.1002/j.1460-2075.1990.tb07416.x; RA Mosthaf L., Grako K., Dull T.J., Coussens L., Ullrich A., McClain D.A.; RT "Functionally distinct insulin receptors generated by tissue-specific RT alternative splicing."; RL EMBO J. 9:2409-2413(1990). RN [16] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 895-1085. RX PubMed=2566545; DOI=10.2337/diab.38.6.737; RA Elbein S.C.; RT "Molecular and clinical characterization of an insertional polymorphism of RT the insulin-receptor gene."; RL Diabetes 38:737-743(1989). RN [17] RP PROTEIN SEQUENCE OF 927-956; 981-1019; 1182-1194 AND 1352-1369, AND RP PHOSPHORYLATION AT TYR-999; TYR-1355 AND TYR-1361. RC TISSUE=Placenta; RX PubMed=3166375; DOI=10.1042/bj2520607; RA Tavare J.M., Denton R.M.; RT "Studies on the autophosphorylation of the insulin receptor from human RT placenta. Analysis of the sites phosphorylated by two-dimensional peptide RT mapping."; RL Biochem. J. 252:607-615(1988). RN [18] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1006-1123. RX PubMed=2544997; DOI=10.1126/science.2544997; RA Taira M., Taira M., Hashimoto N., Shimada F., Suzuki Y., Kanatsuka A., RA Nakamura F., Ebina Y., Tatibana M., Makino H.; RT "Human diabetes associated with a deletion of the tyrosine kinase domain of RT the insulin receptor."; RL Science 245:63-66(1989). RN [19] RP PARTIAL PROTEIN SEQUENCE. RX PubMed=3447155; RA Fujita-Yamaguchi Y., Hawke D., Shively J.E., Choi S.; RT "Partial amino acid sequence analyses of human placental insulin RT receptor."; RL Protein Seq. Data Anal. 1:3-6(1987). RN [20] RP MUTAGENESIS OF LYS-1057. RX PubMed=3101064; DOI=10.1073/pnas.84.3.704; RA Ebina Y., Araki E., Taira M., Shimada F., Mori M., Craik C.S., Siddle K., RA Pierce S.B., Roth R.A., Rutter W.J.; RT "Replacement of lysine residue 1030 in the putative ATP-binding region of RT the insulin receptor abolishes insulin- and antibody-stimulated glucose RT uptake and receptor kinase activity."; RL Proc. Natl. Acad. Sci. U.S.A. 84:704-708(1987). RN [21] RP MUTAGENESIS OF TYR-999. RX PubMed=2842060; DOI=10.1016/s0092-8674(88)80008-4; RA White M.F., Livingston J.N., Backer J.M., Lauris V., Dull T.J., Ullrich A., RA Kahn C.R.; RT "Mutation of the insulin receptor at tyrosine 960 inhibits signal RT transmission but does not affect its tyrosine kinase activity."; RL Cell 54:641-649(1988). RN [22] RP AUTOPHOSPHORYLATION. RX PubMed=1321605; DOI=10.1016/s0006-291x(05)80799-5; RA Dickens M., Tavare J.M.; RT "Analysis of the order of autophosphorylation of human insulin receptor RT tyrosines 1158, 1162 and 1163."; RL Biochem. Biophys. Res. Commun. 186:244-250(1992). RN [23] RP DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-541. RX PubMed=1472036; DOI=10.1016/0006-291x(92)92250-2; RA Schaeffer L., Ljungqvist L.; RT "Identification of a disulfide bridge connecting the alpha-subunits of the RT extracellular domain of the insulin receptor."; RL Biochem. Biophys. Res. Commun. 189:650-653(1992). RN [24] RP FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R. RX PubMed=8452530; DOI=10.1042/bj2900419; RA Soos M.A., Field C.E., Siddle K.; RT "Purified hybrid insulin/insulin-like growth factor-I receptors bind RT insulin-like growth factor-I, but not insulin, with high affinity."; RL Biochem. J. 290:419-426(1993). RN [25] RP FUNCTION, AND INTERACTION WITH PIK3R1. RX PubMed=8276809; DOI=10.1016/s0021-9258(17)42304-0; RA Van Horn D.J., Myers M.G. Jr., Backer J.M.; RT "Direct activation of the phosphatidylinositol 3'-kinase by the insulin RT receptor."; RL J. Biol. Chem. 269:29-32(1994). RN [26] RP INTERACTION WITH IRS1 AND SHC1, AND MUTAGENESIS OF LEU-991; TYR-992; RP ASN-996; 996-ASN-PRO-997; PRO-997; TYR-999; LEU-1000 AND ALA-1002. RX PubMed=7559478; DOI=10.1074/jbc.270.40.23258; RA He W., O'Neill T.J., Gustafson T.A.; RT "Distinct modes of interaction of SHC and insulin receptor substrate-1 with RT the insulin receptor NPEY region via non-SH2 domains."; RL J. Biol. Chem. 270:23258-23262(1995). RN [27] RP INTERACTION WITH IRS1; SHC1 AND PIK3R1, AND MUTAGENESIS OF ASN-996; RP PRO-997; GLU-998; TYR-999 AND LYS-1057. RX PubMed=7537849; DOI=10.1128/mcb.15.5.2500; RA Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.; RT "Phosphotyrosine-dependent interaction of SHC and insulin receptor RT substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 RT domain."; RL Mol. Cell. Biol. 15:2500-2508(1995). RN [28] RP FORMATION OF A HYBRID RECEPTOR WITH IGF1R, AND TISSUE SPECIFICITY. RX PubMed=9355755; DOI=10.1042/bj3270209; RA Bailyes E.M., Nave B.T., Soos M.A., Orr S.R., Hayward A.C., Siddle K.; RT "Insulin receptor/IGF-I receptor hybrids are widely distributed in RT mammalian tissues: quantification of individual receptor species by RT selective immunoprecipitation and immunoblotting."; RL Biochem. J. 327:209-215(1997). RN [29] RP FUNCTION IN PHOSPHORYLATION OF STAT5B, MUTAGENESIS OF TYR-999, AND RP INTERACTION WITH STAT5B; IRS1 AND IRS2. RX PubMed=9428692; DOI=10.1111/j.1432-1033.1997.0411a.x; RA Sawka-Verhelle D., Filloux C., Tartare-Deckert S., Mothe I., RA Van Obberghen E.; RT "Identification of Stat 5B as a substrate of the insulin receptor."; RL Eur. J. Biochem. 250:411-417(1997). RN [30] RP INTERACTION WITH PTPRF. RX PubMed=8995282; DOI=10.1074/jbc.272.11.7519; RA Ahmad F., Goldstein B.J.; RT "Functional association between the insulin receptor and the transmembrane RT protein-tyrosine phosphatase LAR in intact cells."; RL J. Biol. Chem. 272:448-457(1997). RN [31] RP INTERACTION WITH PTPRE, AND DEPHOSPHORYLATION BY PTPRE. RX PubMed=8999839; DOI=10.1074/jbc.272.3.1639; RA Bandyopadhyay D., Kusari A., Kenner K.A., Liu F., Chernoff J., RA Gustafson T.A., Kusari J.; RT "Protein-tyrosine phosphatase 1B complexes with the insulin receptor in RT vivo and is tyrosine-phosphorylated in the presence of insulin."; RL J. Biol. Chem. 272:1639-1645(1997). RN [32] RP FORMATION OF A HYBRID RECEPTOR WITH IGF1R, AND TISSUE SPECIFICITY. RX PubMed=9202395; DOI=10.1016/s0303-7207(97)04050-1; RA Federici M., Porzio O., Zucaro L., Fusco A., Borboni P., Lauro D., RA Sesti G.; RT "Distribution of insulin/insulin-like growth factor-I hybrid receptors in RT human tissues."; RL Mol. Cell. Endocrinol. 129:121-126(1997). RN [33] RP TISSUE SPECIFICITY, AND FUNCTION AS RECEPTOR FOR IGFII (ISOFORM SHORT). RX PubMed=10207053; DOI=10.1128/mcb.19.5.3278; RA Frasca F., Pandini G., Scalia P., Sciacca L., Mineo R., Costantino A., RA Goldfine I.D., Belfiore A., Vigneri R.; RT "Insulin receptor isoform A, a newly recognized, high-affinity insulin-like RT growth factor II receptor in fetal and cancer cells."; RL Mol. Cell. Biol. 19:3278-3288(1999). RN [34] RP INTERACTION WITH ENPP1, AND ACTIVITY REGULATION. RX PubMed=10615944; DOI=10.2337/diabetes.49.1.13; RA Maddux B.A., Goldfine I.D.; RT "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs RT via direct interaction with the receptor alpha-subunit."; RL Diabetes 49:13-19(2000). RN [35] RP PHOSPHORYLATION, AND DEPHOSPHORYLATION BY PTPN1 AND PTPN2. RX PubMed=10734133; DOI=10.1074/jbc.275.13.9792; RA Waelchli S., Curchod M.L., Gobert R.P., Arkinstall S., RA Hooft van Huijsduijnen R.; RT "Identification of tyrosine phosphatases that dephosphorylate the insulin RT receptor. A brute force approach based on 'substrate-trapping' mutants."; RL J. Biol. Chem. 275:9792-9796(2000). RN [36] RP INTERACTION WITH GRB7, AND MUTAGENESIS OF LYS-1057; TYR-1189 AND TYR-1190. RX PubMed=10803466; DOI=10.1038/sj.onc.1203469; RA Kasus-Jacobi A., Bereziat V., Perdereau D., Girard J., Burnol A.F.; RT "Evidence for an interaction between the insulin receptor and Grb7. A role RT for two of its binding domains, PIR and SH2."; RL Oncogene 19:2052-2059(2000). RN [37] RP INTERACTION WITH SORBS1. RX PubMed=11374898; DOI=10.1006/geno.2001.6541; RA Lin W.-H., Huang C.-J., Liu M.-W., Chang H.-M., Chen Y.-J., Tai T.-Y., RA Chuang L.-M.; RT "Cloning, mapping, and characterization of the human sorbin and SH3 domain RT containing 1 (SORBS1) gene: a protein associated with c-Abl during insulin RT signaling in the hepatoma cell line Hep3B."; RL Genomics 74:12-20(2001). RN [38] RP CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-1159 AND ARG-1163, AND ACTIVITY RP REGULATION. RX PubMed=11598120; DOI=10.1074/jbc.m107236200; RA Ablooglu A.J., Frankel M., Rusinova E., Ross J.B., Kohanski R.A.; RT "Multiple activation loop conformations and their regulatory properties in RT the insulin receptor's kinase domain."; RL J. Biol. Chem. 276:46933-46940(2001). RN [39] RP INTERACTION WITH GRB14, AND ACTIVITY REGULATION. RX PubMed=11726652; DOI=10.1074/jbc.m106574200; RA Bereziat V., Kasus-Jacobi A., Perdereau D., Cariou B., Girard J., RA Burnol A.F.; RT "Inhibition of insulin receptor catalytic activity by the molecular adapter RT Grb14."; RL J. Biol. Chem. 277:4845-4852(2002). RN [40] RP FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R. RX PubMed=12138094; DOI=10.1074/jbc.m202766200; RA Pandini G., Frasca F., Mineo R., Sciacca L., Vigneri R., Belfiore A.; RT "Insulin/insulin-like growth factor I hybrid receptors have different RT biological characteristics depending on the insulin receptor isoform RT involved."; RL J. Biol. Chem. 277:39684-39695(2002). RN [41] RP INTERACTION WITH GRB10, AND ACTIVITY REGULATION. RX PubMed=12493740; DOI=10.1074/jbc.m208518200; RA Wick K.R., Werner E.D., Langlais P., Ramos F.J., Dong L.Q., Shoelson S.E., RA Liu F.; RT "Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)- RT phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the RT association of IRS-1/IRS-2 with the insulin receptor."; RL J. Biol. Chem. 278:8460-8467(2003). RN [42] RP PHOSPHORYLATION, AND DEPHOSPHORYLATION BY PTPN2. RX PubMed=12612081; DOI=10.1128/mcb.23.6.2096-2108.2003; RA Galic S., Klingler-Hoffmann M., Fodero-Tavoletti M.T., Puryer M.A., RA Meng T.C., Tonks N.K., Tiganis T.; RT "Regulation of insulin receptor signaling by the protein tyrosine RT phosphatase TCPTP."; RL Mol. Cell. Biol. 23:2096-2108(2003). RN [43] RP INTERACTION WITH SOCS7. RX PubMed=16127460; DOI=10.1172/jci23853; RA Banks A.S., Li J., McKeag L., Hribal M.L., Kashiwada M., Accili D., RA Rothman P.B.; RT "Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of RT Langerhans."; RL J. Clin. Invest. 115:2462-2471(2005). RN [44] RP FUNCTION IN PHOSPHORYLATION OF PDPK1, AND INTERACTION WITH PDPK1. RX PubMed=16314505; DOI=10.1128/mcb.25.24.10803-10814.2005; RA Fiory F., Alberobello A.T., Miele C., Oriente F., Esposito I., Corbo V., RA Ruvo M., Tizzano B., Rasmussen T.E., Gammeltoft S., Formisano P., RA Beguinot F.; RT "Tyrosine phosphorylation of phosphoinositide-dependent kinase 1 by the RT insulin receptor is necessary for insulin metabolic signaling."; RL Mol. Cell. Biol. 25:10803-10814(2005). RN [45] RP DEPHOSPHORYLATION BY PTPRE. RX PubMed=15738637; DOI=10.2108/zsj.22.169; RA Nakagawa Y., Aoki N., Aoyama K., Shimizu H., Shimano H., Yamada N., RA Miyazaki H.; RT "Receptor-type protein tyrosine phosphatase epsilon (PTPepsilonM) is a RT negative regulator of insulin signaling in primary hepatocytes and liver."; RL Zool. Sci. 22:169-175(2005). RN [46] RP FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R. RX PubMed=16831875; DOI=10.1074/jbc.m605189200; RA Slaaby R., Schaeffer L., Lautrup-Larsen I., Andersen A.S., Shaw A.C., RA Mathiasen I.S., Brandt J.; RT "Hybrid receptors formed by insulin receptor (IR) and insulin-like growth RT factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity RT irrespective of the IR splice variant."; RL J. Biol. Chem. 281:25869-25874(2006). RN [47] RP REVIEW ON SIGNALING PATHWAYS. RX PubMed=16493415; DOI=10.1038/nrm1837; RA Taniguchi C.M., Emanuelli B., Kahn C.R.; RT "Critical nodes in signalling pathways: insights into insulin action."; RL Nat. Rev. Mol. Cell Biol. 7:85-96(2006). RN [48] RP REVIEW ON REGULATION OF INSR FUNCTION. RX PubMed=17347799; DOI=10.1007/s00018-007-6359-9; RA Youngren J.F.; RT "Regulation of insulin receptor function."; RL Cell. Mol. Life Sci. 64:873-891(2007). RN [49] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-400; TYR-401 AND SER-407, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [50] RP DOMAIN, AND INSULIN-BINDING SITE. RX PubMed=19459609; DOI=10.1021/bi900261q; RA Menting J.G., Ward C.W., Margetts M.B., Lawrence M.C.; RT "A thermodynamic study of ligand binding to the first three domains of the RT human insulin receptor: relationship between the receptor alpha-chain C- RT terminal peptide and the site 1 insulin mimetic peptides."; RL Biochemistry 48:5492-5500(2009). RN [51] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-242 AND ASN-541. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [52] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [53] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-445 AND ASN-920. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [54] RP INTERACTION WITH NCK1, AND PHOSPHORYLATION AT TYR-1189 AND TYR-1190. RX PubMed=21707536; DOI=10.1042/bj20110799; RA Wu C.L., Buszard B., Teng C.H., Chen W.L., Warr C.G., Tiganis T., RA Meng T.C.; RT "Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling."; RL Biochem. J. 439:151-159(2011). RN [55] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [56] RP INTERACTION WITH CCDC88A AND GNAI3. RX PubMed=25187647; DOI=10.1091/mbc.e14-05-0978; RA Lin C., Ear J., Midde K., Lopez-Sanchez I., Aznar N., Garcia-Marcos M., RA Kufareva I., Abagyan R., Ghosh P.; RT "Structural basis for activation of trimeric Gi proteins by multiple growth RT factor receptors via GIV/Girdin."; RL Mol. Biol. Cell 25:3654-3671(2014). RN [57] RP INTERACTION WITH SORL1. RX PubMed=27322061; DOI=10.1172/jci84708; RA Schmidt V., Schulz N., Yan X., Schuermann A., Kempa S., Kern M., RA Blueher M., Poy M.N., Olivecrona G., Willnow T.E.; RT "SORLA facilitates insulin receptor signaling in adipocytes and exacerbates RT obesity."; RL J. Clin. Invest. 126:2706-2720(2016). RN [58] RP SUBUNIT. RX PubMed=27617429; DOI=10.1038/nsmb.3292; RA Menting J.G., Gajewiak J., MacRaild C.A., Chou D.H., Disotuar M.M., RA Smith N.A., Miller C., Erchegyi J., Rivier J.E., Olivera B.M., Forbes B.E., RA Smith B.J., Norton R.S., Safavi-Hemami H., Lawrence M.C.; RT "A minimized human insulin-receptor-binding motif revealed in a Conus RT geographus venom insulin."; RL Nat. Struct. Mol. Biol. 23:916-920(2016). RN [59] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310. RX PubMed=7997262; DOI=10.1038/372746a0; RA Hubbard S.R., Wei L., Ellis L., Hendrickson W.A.; RT "Crystal structure of the tyrosine kinase domain of the human insulin RT receptor."; RL Nature 372:746-754(1994). RN [60] RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP RP ANALOG AND IRS1 PEPTIDE, CATALYTIC ACTIVITY, ACTIVE SITE, RP AUTOPHOSPHORYLATION, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND RP TYR-1190. RX PubMed=9312016; DOI=10.1093/emboj/16.18.5572; RA Hubbard S.R.; RT "Crystal structure of the activated insulin receptor tyrosine kinase in RT complex with peptide substrate and ATP analog."; RL EMBO J. 16:5572-5581(1997). RN [61] RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP RP ANALOG, AND CATALYTIC ACTIVITY. RX PubMed=11124964; DOI=10.1074/jbc.m010161200; RA Till J.H., Ablooglu A.J., Frankel M., Bishop S.M., Kohanski R.A., RA Hubbard S.R.; RT "Crystallographic and solution studies of an activation loop mutant of the RT insulin receptor tyrosine kinase: insights into kinase mechanism."; RL J. Biol. Chem. 276:10049-10055(2001). RN [62] RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1005-1298 OF MUTANT ASN-1159, RP CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF TYR-1011. RX PubMed=12707268; DOI=10.1074/jbc.m302425200; RA Li S., Covino N.D., Stein E.G., Till J.H., Hubbard S.R.; RT "Structural and biochemical evidence for an autoinhibitory role for RT tyrosine 984 in the juxtamembrane region of the insulin receptor."; RL J. Biol. Chem. 278:26007-26014(2003). RN [63] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP RP ANALOG AND SH2B2, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190. RX PubMed=14690593; DOI=10.1016/s1097-2765(03)00487-8; RA Hu J., Liu J., Ghirlando R., Saltiel A.R., Hubbard S.R.; RT "Structural basis for recruitment of the adaptor protein APS to the RT activated insulin receptor."; RL Mol. Cell 12:1379-1389(2003). RN [64] RP X-RAY CRYSTALLOGRAPHY (3.20 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH GRB14, RP INTERACTION WITH GRB14, AUTOPHOSPHORYLATION, AND PHOSPHORYLATION AT RP TYR-1185; TYR-1189 AND TYR-1190. RX PubMed=16246733; DOI=10.1016/j.molcel.2005.09.001; RA Depetris R.S., Hu J., Gimpelevich I., Holt L.J., Daly R.J., Hubbard S.R.; RT "Structural basis for inhibition of the insulin receptor by the adaptor RT protein Grb14."; RL Mol. Cell 20:325-333(2005). RN [65] RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH PTPN1, RP AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190. RX PubMed=16271887; DOI=10.1016/j.str.2005.07.019; RA Li S., Depetris R.S., Barford D., Chernoff J., Hubbard S.R.; RT "Crystal structure of a complex between protein tyrosine phosphatase 1B and RT the insulin receptor tyrosine kinase."; RL Structure 13:1643-1651(2005). RN [66] RP X-RAY CRYSTALLOGRAPHY (3.8 ANGSTROMS) OF 28-943 IN COMPLEX WITH INSULIN RP ANALOG, DOMAIN, AND DISULFIDE BONDS. RX PubMed=16957736; DOI=10.1038/nature05106; RA McKern N.M., Lawrence M.C., Streltsov V.A., Lou M.Z., Adams T.E., RA Lovrecz G.O., Elleman T.C., Richards K.M., Bentley J.D., Pilling P.A., RA Hoyne P.A., Cartledge K.A., Pham T.M., Lewis J.L., Sankovich S.E., RA Stoichevska V., Da Silva E., Robinson C.P., Frenkel M.J., Sparrow L.G., RA Fernley R.T., Epa V.C., Ward C.W.; RT "Structure of the insulin receptor ectodomain reveals a folded-over RT conformation."; RL Nature 443:218-221(2006). RN [67] RP X-RAY CRYSTALLOGRAPHY (2.32 ANGSTROMS) OF 28-512, GLYCOSYLATION AT ASN-43; RP ASN-52; ASN-138; ASN-242; ASN-282; ASN-364; ASN-424 AND ASN-445, AND RP DISULFIDE BONDS. RX PubMed=16894147; DOI=10.1073/pnas.0605395103; RA Lou M., Garrett T.P., McKern N.M., Hoyne P.A., Epa V.C., Bentley J.D., RA Lovrecz G.O., Cosgrove L.J., Frenkel M.J., Ward C.W.; RT "The first three domains of the insulin receptor differ structurally from RT the insulin-like growth factor 1 receptor in the regions governing ligand RT specificity."; RL Proc. Natl. Acad. Sci. U.S.A. 103:12429-12434(2006). RN [68] RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP AND RP IRS2, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-1185; TYR-1189 AND RP TYR-1190, AND INTERACTION WITH IRS2. RX PubMed=18278056; DOI=10.1038/nsmb.1388; RA Wu J., Tseng Y.D., Xu C.F., Neubert T.A., White M.F., Hubbard S.R.; RT "Structural and biochemical characterization of the KRLB region in insulin RT receptor substrate-2."; RL Nat. Struct. Mol. Biol. 15:251-258(2008). RN [69] RP X-RAY CRYSTALLOGRAPHY (3.25 ANGSTROMS) OF 1009-1310 IN COMPLEX WITH RP INHIBITORY PEPTIDE, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190. RX PubMed=18767165; DOI=10.1002/prot.22207; RA Katayama N., Orita M., Yamaguchi T., Hisamichi H., Kuromitsu S., RA Kurihara H., Sakashita H., Matsumoto Y., Fujita S., Niimi T.; RT "Identification of a key element for hydrogen-bonding patterns between RT protein kinases and their inhibitors."; RL Proteins 73:795-801(2008). RN [70] RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH RP SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY. RX PubMed=19071018; DOI=10.1016/j.bmcl.2008.11.077; RA Chamberlain S.D., Redman A.M., Wilson J.W., Deanda F., Shotwell J.B., RA Gerding R., Lei H., Yang B., Stevens K.L., Hassell A.M., Shewchuk L.M., RA Leesnitzer M.A., Smith J.L., Sabbatini P., Atkins C., Groy A., Rowand J.L., RA Kumar R., Mook R.A. Jr., Moorthy G., Patnaik S.; RT "Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R RT tyrosine kinase inhibitors towards JNK selectivity."; RL Bioorg. Med. Chem. Lett. 19:360-364(2009). RN [71] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH RP SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY. RX PubMed=19056263; DOI=10.1016/j.bmcl.2008.11.046; RA Chamberlain S.D., Wilson J.W., Deanda F., Patnaik S., Redman A.M., Yang B., RA Shewchuk L., Sabbatini P., Leesnitzer M.A., Groy A., Atkins C., Gerding R., RA Hassell A.M., Lei H., Mook R.A. Jr., Moorthy G., Rowand J.L., Stevens K.L., RA Kumar R., Shotwell J.B.; RT "Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: potent RT inhibitors of the IGF-1R receptor tyrosine kinase."; RL Bioorg. Med. Chem. Lett. 19:469-473(2009). RN [72] RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 1017-1322 IN COMPLEX WITH RP SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY. RX PubMed=19394223; DOI=10.1016/j.bmcl.2008.12.110; RA Patnaik S., Stevens K.L., Gerding R., Deanda F., Shotwell J.B., Tang J., RA Hamajima T., Nakamura H., Leesnitzer M.A., Hassell A.M., Shewchuck L.M., RA Kumar R., Lei H., Chamberlain S.D.; RT "Discovery of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines as potent RT inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) tyrosine RT kinase."; RL Bioorg. Med. Chem. Lett. 19:3136-3140(2009). RN [73] RP X-RAY CRYSTALLOGRAPHY (3.80 ANGSTROMS) OF 28-956, INSULIN-BINDING REGION, RP AND DISULFIDE BONDS. RX PubMed=20348418; DOI=10.1073/pnas.1001813107; RA Smith B.J., Huang K., Kong G., Chan S.J., Nakagawa S., Menting J.G., RA Hu S.Q., Whittaker J., Steiner D.F., Katsoyannis P.G., Ward C.W., RA Weiss M.A., Lawrence M.C.; RT "Structural resolution of a tandem hormone-binding element in the insulin RT receptor and its implications for design of peptide agonists."; RL Proc. Natl. Acad. Sci. U.S.A. 107:6771-6776(2010). RN [74] RP X-RAY CRYSTALLOGRAPHY (3.9 ANGSTROMS) OF 28-620 IN COMPLEX WITH INSULIN, RP DOMAIN, GLYCOSYLATION AT ASN-43; ASN-52; ASN-138; ASN-242 AND ASN-282, AND RP DISULFIDE BONDS. RX PubMed=23302862; DOI=10.1038/nature11781; RA Menting J.G., Whittaker J., Margetts M.B., Whittaker L.J., Kong G.K., RA Smith B.J., Watson C.J., Zakova L., Kletvikova E., Jiracek J., Chan S.J., RA Steiner D.F., Dodson G.G., Brzozowski A.M., Weiss M.A., Ward C.W., RA Lawrence M.C.; RT "How insulin engages its primary binding site on the insulin receptor."; RL Nature 493:241-245(2013). RN [75] RP VARIANT IRAN TYPE A SER-762. RX PubMed=3283938; DOI=10.1126/science.3283938; RA Yoshimasa Y., Seino S., Whittaker J., Kakehi T., Kosaki A., Kuzuya H., RA Imura H., Bell G.I., Steiner D.F.; RT "Insulin-resistant diabetes due to a point mutation that prevents insulin RT proreceptor processing."; RL Science 240:784-787(1988). RN [76] RP VARIANT LEPRCH GLU-487. RX PubMed=2834824; DOI=10.1126/science.2834824; RA Kadowaki T., Bevins C., Cama A., Ojamaa K., Marcus-Samuels B., Kadowaki H., RA Beitz L., McKeon C., Taylor S.I.; RT "Two mutant alleles of the insulin receptor gene in a patient with extreme RT insulin resistance."; RL Science 240:787-790(1988). RN [77] RP VARIANT LEPRCH PRO-260. RX PubMed=2479553; DOI=10.1002/j.1460-2075.1989.tb08387.x; RA Klinkhamer M.P., Groen N.A., van der Zon G.C.M., Lindhout D., RA Sandkuyl L.A., Krans H.M.J., Moeller W., Maassen J.A.; RT "A leucine-to-proline mutation in the insulin receptor in a family with RT insulin resistance."; RL EMBO J. 8:2503-2507(1989). RN [78] RP VARIANT IRAN TYPE A VAL-1035. RX PubMed=2544998; DOI=10.1126/science.2544998; RA Odawara M., Kadowaki T., Yamamoto R., Shibasaki Y., Tobe K., Accili D., RA Bevins C., Mikami Y., Matsuura N., Akanuma Y., Takaku F., Taylor S.I., RA Kasuga M.; RT "Human diabetes associated with a mutation in the tyrosine kinase domain of RT the insulin receptor."; RL Science 245:66-68(1989). RN [79] RP VARIANT IRAN TYPE A THR-1161. RX PubMed=2168397; DOI=10.1016/s0021-9258(18)77212-8; RA Moller D.E., Yokota A., White M.F., Pazianos A.G., Flier J.S.; RT "A naturally occurring mutation of insulin receptor alanine 1134 impairs RT tyrosine kinase function and is associated with dominantly inherited RT insulin resistance."; RL J. Biol. Chem. 265:14979-14985(1990). RN [80] RP CHARACTERIZATION OF VARIANT RMS LYS-42. RX PubMed=2121734; DOI=10.1016/s0021-9258(17)30636-1; RA Kadowaki T., Kadowaki H., Accili D., Taylor S.I.; RT "Substitution of lysine for asparagine at position 15 in the alpha-subunit RT of the human insulin receptor. A mutation that impairs transport of RT receptors to the cell surface and decreases the affinity of insulin RT binding."; RL J. Biol. Chem. 265:19143-19150(1990). RN [81] RP VARIANT RMS LYS-42, VARIANT LEPRCH ARG-236, AND VARIANT IRAN TYPE A RP SER-489. RX PubMed=2365819; DOI=10.1172/jci114693; RA Kadowaki T., Kadowaki H., Rechler M.M., Serrano-Rios M., Roth J., RA Gorden P., Taylor S.I.; RT "Five mutant alleles of the insulin receptor gene in patients with genetic RT forms of insulin resistance."; RL J. Clin. Invest. 86:254-264(1990). RN [82] RP VARIANT IRAN TYPE A SER-1227. RX PubMed=1963473; DOI=10.1210/mend-4-8-1183; RA Moller D.E., Yokota A., Ginsberg-Fellner F., Flier J.S.; RT "Functional properties of a naturally occurring Trp1200-->Ser1200 mutation RT of the insulin receptor."; RL Mol. Endocrinol. 4:1183-1191(1990). RN [83] RP VARIANT GLU-1095. RX PubMed=2040394; DOI=10.2337/diab.40.6.777; RA O'Rahilly S., Choi W.H., Patel P., Turner R.C., Flier J.S., Moller D.E.; RT "Detection of mutations in insulin-receptor gene in NIDDM patients by RT analysis of single-stranded conformation polymorphisms."; RL Diabetes 40:777-782(1991). RN [84] RP VARIANT IRAN TYPE A GLN-1020. RX PubMed=2002058; DOI=10.1016/s0021-9258(19)67781-1; RA Kusari J., Takata Y., Hatada E., Freidenberg G., Kolterman O., RA Olefsky J.M.; RT "Insulin resistance and diabetes due to different mutations in the tyrosine RT kinase domain of both insulin receptor gene alleles."; RL J. Biol. Chem. 266:5260-5267(1991). RN [85] RP VARIANT INS RESISTANCE ILE-1180. RX PubMed=1890161; DOI=10.1210/jcem-73-4-894; RA Cama A., de la Luz Sierra M., Ottini L., Kadowaki T., Gorden P., RA Imperato-Mcginley J., Taylor S.I.; RT "A mutation in the tyrosine kinase domain of the insulin receptor RT associated with insulin resistance in an obese woman."; RL J. Clin. Endocrinol. Metab. 73:894-901(1991). RN [86] RP VARIANTS LEPRCH ALA-55 AND ARG-393. RX PubMed=1607067; DOI=10.2337/diab.41.4.408; RA Barbetti F., Gejman P.V., Taylor S.I., Raben N., Cama A., Bonora E., RA Pizzo P., Moghetti P., Muggeo M., Roth J.; RT "Detection of mutations in insulin receptor gene by denaturing gradient gel RT electrophoresis."; RL Diabetes 41:408-415(1992). RN [87] RP VARIANT T2D GLN-1191. RX PubMed=1607076; DOI=10.2337/diab.41.4.521; RA Cocozza S., Porcellini A., Riccardi G., Monticelli A., Condorelli G., RA Ferrara A., Pianese L., Miele C., Capaldo B., Beguinot F., Varrone S.; RT "NIDDM associated with mutation in tyrosine kinase domain of insulin RT receptor gene."; RL Diabetes 41:521-526(1992). RN [88] RP VARIANT IRAN TYPE A LEU-1205. RX PubMed=1563582; DOI=10.1007/bf00400927; RA Kim H., Kadowaki H., Sakura H., Odawara M., Momomura K., Takahashi Y., RA Miyazaki Y., Ohtani T., Akanuma Y., Yazaki Y., Kasuga M., Taylor S.I., RA Kadowaki T.; RT "Detection of mutations in the insulin receptor gene in patients with RT insulin resistance by analysis of single-stranded conformational RT polymorphisms."; RL Diabetologia 35:261-266(1992). RN [89] RP VARIANT LEPRCH ARG-58. RX PubMed=1730625; DOI=10.1016/s0021-9258(18)48459-1; RA van der Vorm E.R., van der Zon G.C.M., Moeller W., Krans H.M.J., RA Lindhout D., Maassen J.A.; RT "An Arg for Gly substitution at position 31 in the insulin receptor, linked RT to insulin resistance, inhibits receptor processing and transport."; RL J. Biol. Chem. 267:66-71(1992). RN [90] RP VARIANT T2D GLN-1158. RX PubMed=1470163; RA Kasuga M., Kishimoto M., Hashiramoto M., Yonezawa K., Kazumi T., Hagino H., RA Shii K.; RT "Insulin receptor Arg1131-->Gln: a novel mutation in the catalytic loop of RT insulin receptor observed in insulin resistant diabetes."; RL Nihon Geka Gakkai Zasshi 93:968-971(1992). RN [91] RP VARIANT MET-1012. RX PubMed=8432414; DOI=10.2337/diab.42.3.429; RA Elbein S.C., Sorensen L.K., Schumacher M.C.; RT "Methionine for valine substitution in exon 17 of the insulin receptor gene RT in a pedigree with familial NIDDM."; RL Diabetes 42:429-434(1993). RN [92] RP VARIANT IRAN TYPE A ASP-1075. RX PubMed=8243830; DOI=10.2337/diab.42.12.1837; RA Haruta T., Takata Y., Iwanishi M., Maegawa H., Imamura T., Egawa K., RA Itazu T., Kobayashi M.; RT "Ala1048-->Asp mutation in the kinase domain of insulin receptor causes RT defective kinase activity and insulin resistance."; RL Diabetes 42:1837-1844(1993). RN [93] RP VARIANT MET-1012. RX PubMed=8458533; DOI=10.1007/bf00400701; RA van der Vorm E.R., Kuipers A., Bonenkamp J.W., Kleijer W.J., RA van Maldergem L., Herwig J., Maassen J.A.; RT "Patients with lipodystrophic diabetes mellitus of the Seip-Berardinelli RT type, express normal insulin receptors."; RL Diabetologia 36:172-174(1993). RN [94] RP VARIANT INS RESISTANCE LEU-1220. RX PubMed=8390949; DOI=10.1007/bf00402277; RA Iwanishi M., Haruta T., Takata Y., Ishibashi O., Sasaoka T., Egawa K., RA Imamura T., Naitou K., Itazu T., Kobayashi M.; RT "A mutation (Trp1193-->Leu1193) in the tyrosine kinase domain of the RT insulin receptor associated with type A syndrome of insulin resistance."; RL Diabetologia 36:414-422(1993). RN [95] RP VARIANT INS RESISTANCE LEU-220. RX PubMed=8242067; DOI=10.1093/hmg/2.9.1437; RA Carrera P., Cordera R., Ferrari M., Cremonesi L., Taramelli R., RA Andraghetti G., Carducci C., Dozio N., Pozza G., Taylor S.I., Micossi P., RA Barbetti F.; RT "Substitution of Leu for Pro-193 in the insulin receptor in a patient with RT a genetic form of severe insulin resistance."; RL Hum. Mol. Genet. 2:1437-1441(1993). RN [96] RP CHARACTERIZATION OF VARIANT IRAN TYPE A GLU-1162. RX PubMed=8096518; DOI=10.1016/s0021-9258(18)53063-5; RA Cama A., de la Luz Sierra M., Quon M.J., Ottini L., Gorden P., Taylor S.I.; RT "Substitution of glutamic acid for alanine 1135 in the putative 'catalytic RT loop' of the tyrosine kinase domain of the human insulin receptor. A RT mutation that impairs proteolytic processing into subunits and inhibits RT receptor tyrosine kinase activity."; RL J. Biol. Chem. 268:8060-8069(1993). RN [97] RP VARIANT IRAN TYPE A VAL-409. RX PubMed=8388389; DOI=10.1016/s0021-9258(18)82120-2; RA Lebrun C., Baron V., Kaliman P., Gautier N., Dolais-Kitabgi J., RA Taylor S.I., Accili D., van Obberghen E.; RT "Antibodies to the extracellular receptor domain restore the hormone- RT insensitive kinase and conformation of the mutant insulin receptor valine RT 382."; RL J. Biol. Chem. 268:11272-11277(1993). RN [98] RP VARIANT LEPRCH MET-146. RX PubMed=8326490; DOI=10.1136/jmg.30.6.470; RA Al-Gazali L.I., Khalil M., Devadas K.; RT "A syndrome of insulin resistance resembling leprechaunism in five sibs of RT consanguineous parents."; RL J. Med. Genet. 30:470-475(1993). RN [99] RP VARIANT LEPRCH PRO-113. RX PubMed=8419945; DOI=10.1073/pnas.90.1.60; RA Longo N., Langley S.D., Griffin L.D., Elsas L.J.; RT "Activation of glucose transport by a natural mutation in the human insulin RT receptor."; RL Proc. Natl. Acad. Sci. U.S.A. 90:60-64(1993). RN [100] RP VARIANT IRAN TYPE A GLN-1201. RX PubMed=8288049; DOI=10.2337/diab.43.2.247; RA Moller D.E., Cohen O., Yamaguchi Y., Assiz R., Grigorescu F., Eberle A., RA Morrow L.A., Moses A.C., Flier J.S.; RT "Prevalence of mutations in the insulin receptor gene in subjects with RT features of the type A syndrome of insulin resistance."; RL Diabetes 43:247-255(1994). RN [101] RP VARIANT RMS SYNDROME LEU-350, VARIANTS IRAN TYPE A LEU-1205 AND GLN-1378, RP AND VARIANT MET-1012. RX PubMed=8314008; DOI=10.2337/diab.43.3.357; RA Krook A., Kumar S., Laing I., Boulton A.J., Wass J.A., O'Rahilly S.; RT "Molecular scanning of the insulin receptor gene in syndromes of insulin RT resistance."; RL Diabetes 43:357-368(1994). RN [102] RP CHARACTERIZATION OF VARIANT IRAN TYPE A GLN-1201. RX PubMed=8082780; DOI=10.1016/0014-5793(94)00876-0; RA Moritz W., Froesch E.R., Boeni-Schnetzler M.; RT "Functional properties of a heterozygous mutation (Arg1174-->Gln) in the RT tyrosine kinase domain of the insulin receptor from a type A insulin RT resistant patient."; RL FEBS Lett. 351:276-280(1994). RN [103] RP VARIANT LEPRCH SER-439. RX PubMed=8188715; DOI=10.1016/s0021-9258(17)36788-1; RA van der Vorm E.R., Kuipers A., Kielkopf-Renner S., Krans H.M.J., Moller W., RA Maassen J.A.; RT "A mutation in the insulin receptor that impairs proreceptor processing but RT not insulin binding."; RL J. Biol. Chem. 269:14297-14302(1994). RN [104] RP CHARACTERIZATION OF VARIANTS IRAN TYPE A ASP-1206 AND LEU-1220. RX PubMed=7983039; DOI=10.1016/s0021-9258(18)47384-x; RA Imamura T., Takata Y., Sasaoka T., Takada Y., Morioka H., Haruta T., RA Sawa T., Iwanishi M., Hu Y.G., Suzuki Y., Hamada J., Kobayashi M.; RT "Two naturally occurring mutations in the kinase domain of insulin receptor RT accelerate degradation of the insulin receptor and impair the kinase RT activity."; RL J. Biol. Chem. 269:31019-31027(1994). RN [105] RP VARIANT LEPRCH MET-146. RX PubMed=7815442; DOI=10.1136/jmg.31.9.715; RA Hone J., Accili D., al-Gazali L.I., Lestringant G., Orban T., Taylor S.I.; RT "Homozygosity for a new mutation (Ile119-->Met) in the insulin receptor RT gene in five sibs with familial insulin resistance."; RL J. Med. Genet. 31:715-716(1994). RN [106] RP VARIANT T2D ALA-858, AND VARIANT CYS-1361. RX PubMed=7657032; DOI=10.2337/diab.44.9.1081; RA Kan M., Kanai F., Iida M., Jinnouchi H., Todaka M., Imanaka T., Ito K., RA Nishioka Y., Ohnishi T., Kamohara S., Hayashi H., Murakami T., Kagawa S., RA Sano H., Hashimoto N., Yoshida S., Makino H., Ebina Y.; RT "Frequency of mutations of insulin receptor gene in Japanese patients with RT NIDDM."; RL Diabetes 44:1081-1086(1995). RN [107] RP VARIANT LEPRCH ASN-308 DEL. RX PubMed=7538143; DOI=10.1210/jcem.80.5.7538143; RA Longo N., Langley S.D., Griffin L.D., Elsas L.J.; RT "Two mutations in the insulin receptor gene of a patient with RT leprechaunism: application to prenatal diagnosis."; RL J. Clin. Endocrinol. Metab. 80:1496-1501(1995). RN [108] RP VARIANT PHE-1023. RX PubMed=8890729; DOI=10.1530/eje.0.1350357; RA Moritz W., Boeni-Schnetzler M., Stevens W., Froesch E.R., Levy J.R.; RT "In-frame exon 2 deletion in insulin receptor RNA in a family with extreme RT insulin resistance in association with defective insulin binding: a case RT report."; RL Eur. J. Endocrinol. 135:357-363(1996). RN [109] RP VARIANT LEPRCH ASN-308 DEL. RX PubMed=8636294; DOI=10.1210/jcem.81.2.8636294; RA Desbois-Mouthon C., Sert-Langeron C., Magre J., Oreal E., Blivet M.J., RA Flori E., Besmond C., Capeau J., Caron M.; RT "Deletion of Asn281 in the alpha-subunit of the human insulin receptor RT causes constitutive activation of the receptor and insulin RT desensitization."; RL J. Clin. Endocrinol. Metab. 81:719-727(1996). RN [110] RP VARIANT MET-1012. RX PubMed=9199575; DOI=10.1086/515464; RA Hansen L., Hansen T., Clausen J.O., Echwald S.M., Urhammer S.A., RA Rasmussen S.K., Pedersen O.; RT "The Val985Met insulin-receptor variant in the Danish Caucasian population: RT lack of associations with non-insulin-dependent diabetes mellitus or RT insulin resistance."; RL Am. J. Hum. Genet. 60:1532-1535(1997). RN [111] RP VARIANTS IRAN TYPE A GLY-86 AND PRO-89. RX PubMed=9175790; DOI=10.1006/bbrc.1997.6695; RA Rouard M., Macari F., Bouix O., Lautier C., Brun J.F., Lefebvre P., RA Renard E., Bringer J., Jaffiol C., Grigorescu F.; RT "Identification of two novel insulin receptor mutations, Asp59Gly and RT Leu62Pro, in type A syndrome of extreme insulin resistance."; RL Biochem. Biophys. Res. Commun. 234:764-768(1997). RN [112] RP CHARACTERIZATION OF VARIANT LEPRCH MET-937. RX PubMed=9299395; DOI=10.1006/bbrc.1997.7181; RA Kadowaki H., Takahashi Y., Ando A., Momomura K., Kaburagi Y., Quin J.D., RA MacCuish A.C., Koda N., Fukushima Y., Taylor S.I., Akanuma Y., Yazaki Y., RA Kadowaki T.; RT "Four mutant alleles of the insulin receptor gene associated with genetic RT syndromes of extreme insulin resistance."; RL Biochem. Biophys. Res. Commun. 237:516-520(1997). RN [113] RP VARIANTS LEPRCH TRP-1119 AND LYS-1206. RX PubMed=9249867; RX DOI=10.1002/(sici)1097-0223(199707)17:7<657::aid-pd132>3.3.co;2-#; RA Desbois-Mouthon C., Girodon E., Ghanem N., Caron M., Pennerath A., RA Conteville P., Magre J., Besmond C., Goossens M., Capeau J., Amselem S.; RT "Molecular analysis of the insulin receptor gene for prenatal diagnosis of RT leprechaunism in two families."; RL Prenat. Diagn. 17:657-663(1997). RN [114] RP VARIANTS LEPRCH TYR-301 AND TRP-1201. RX PubMed=9703342; DOI=10.2337/diab.47.8.1362; RA Whitehead J.P., Soos M.A., Jackson R., Tasic V., Kocova M., O'Rahilly S.; RT "Multiple molecular mechanisms of insulin receptor dysfunction in a patient RT with Donohue syndrome."; RL Diabetes 47:1362-1364(1998). RN [115] RP VARIANTS RMS THR-1143 AND TRP-1158. RX PubMed=10443650; DOI=10.1210/jcem.84.8.5902; RA Longo N., Wang Y., Pasquali M.; RT "Progressive decline in insulin levels in Rabson-Mendenhall syndrome."; RL J. Clin. Endocrinol. Metab. 84:2623-2629(1999). RN [116] RP VARIANTS IRAN TYPE A LEU-167 AND VAL-1055. RX PubMed=10733238; DOI=10.1034/j.1399-0004.2000.570110.x; RA Rique S., Nogues C., Ibanez L., Marcos M.V., Ferragut J., Carrascosa A., RA Potau N.; RT "Identification of three novel mutations in the insulin receptor gene in RT type A insulin resistant patients."; RL Clin. Genet. 57:67-69(2000). RN [117] RP VARIANT IRAN TYPE A TYR-280. RX PubMed=11260230; DOI=10.1034/j.1399-0004.2001.590309.x; RA Osawa H., Nishimiya T., Ochi M., Niiya T., Onuma H., Kitamuro F., Kaino Y., RA Kida K., Makino H.; RT "Identification of novel C253Y missense and Y864X nonsense mutations in the RT insulin receptor gene in type A insulin-resistant patients."; RL Clin. Genet. 59:194-197(2001). RN [118] RP VARIANT IRAN TYPE A CYS-279. RX PubMed=12107746; DOI=10.1007/s00125-002-0798-5; RA Hamer I., Foti M., Emkey R., Cordier-Bussat M., Philippe J., De Meyts P., RA Maeder C., Kahn C.R., Carpentier J.-L.; RT "An arginine to cysteine(252) mutation in insulin receptors from a patient RT with severe insulin resistance inhibits receptor internalisation but RT preserves signalling events."; RL Diabetologia 45:657-667(2002). RN [119] RP CHARACTERIZATION OF VARIANTS LEPRCH PRO-113; VAL-119; ASN-308 DEL; THR-925 RP AND TRP-926, AND VARIANTS RMS THR-997; THR-1143; TRP-1158 AND TRP-1201. RX PubMed=12023989; DOI=10.1093/hmg/11.12.1465; RA Longo N., Wang Y., Smith S.A., Langley S.D., DiMeglio L.A., RA Giannella-Neto D.; RT "Genotype-phenotype correlation in inherited severe insulin resistance."; RL Hum. Mol. Genet. 11:1465-1475(2002). RN [120] RP VARIANT LEPRCH VAL-362 DEL. RX PubMed=12538626; DOI=10.1210/en.2002-220815; RA George S., Johansen A., Soos M.A., Mortensen H., Gammeltoft S., Saudek V., RA Siddle K., Hansen L., O'Rahilly S.; RT "Deletion of V335 from the L2 domain of the insulin receptor results in a RT conformationally abnormal receptor that is unable to bind insulin and RT causes Donohue's syndrome in a human subject."; RL Endocrinology 144:631-637(2003). RN [121] RP VARIANT IRAN TYPE A HIS-279, VARIANTS LEPRCH GLN-120; LEU-350; ASP-458 AND RP TRP-1119, CHARACTERIZATION OF VARIANT IRAN TYPE A HIS-279, AND RP CHARACTERIZATION OF VARIANTS LEPRCH GLN-120 AND ASP-458. RX PubMed=12970295; DOI=10.1210/jc.2003-030034; RA Maassen J.A., Tobias E.S., Kayserilli H., Tukel T., Yuksel-Apak M., RA D'Haens E., Kleijer W.J., Fery F., van der Zon G.C.M.; RT "Identification and functional assessment of novel and known insulin RT receptor mutations in five patients with syndromes of severe insulin RT resistance."; RL J. Clin. Endocrinol. Metab. 88:4251-4257(2003). RN [122] RP VARIANT HHF5 GLN-1201. RX PubMed=15161766; DOI=10.2337/diabetes.53.6.1592; RA Hoejlund K., Hansen T., Lajer M., Henriksen J.E., Levin K., Lindholm J., RA Pedersen O., Bech-Nielsen H.; RT "A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia RT linked to a mutation in the human insulin receptor gene."; RL Diabetes 53:1592-1598(2004). RN [123] RP VARIANTS RMS ARG-236 AND SER-386, AND CHARACTERIZATION OF VARIANTS RMS RP ARG-236 AND SER-386. RX PubMed=17201797; DOI=10.1111/j.1365-2265.2006.02678.x; RA Tuthill A., Semple R.K., Day R., Soos M.A., Sweeney E., Seymour P.J., RA Didi M., O'Rahilly S.; RT "Functional characterization of a novel insulin receptor mutation RT contributing to Rabson-Mendenhall syndrome."; RL Clin. Endocrinol. (Oxf.) 66:21-26(2007). RN [124] RP VARIANTS [LARGE SCALE ANALYSIS] ARG-228; ARG-695; SER-811; MET-1012; RP VAL-1065 AND ALA-1282. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [125] RP VARIANTS LEPRCH CYS-818 AND 890-ARG--SER-1382 DEL. RX PubMed=22768670; DOI=10.1515/jpem-2011-0448; RA Nobile S., Semple R.K., Carnielli V.P.; RT "A novel mutation of the insulin receptor gene in a preterm infant with RT Donohue syndrome and heart failure."; RL J. Pediatr. Endocrinol. Metab. 25:363-366(2012). RN [126] RP VARIANTS LEPRCH THR-56 AND TYR-286, AND CHARACTERIZATION OF VARIANTS LEPRCH RP THR-56 AND TYR-286. RX PubMed=24498630; DOI=10.1002/mgg3.43; RA Falik Zaccai T.C., Kalfon L., Klar A., Elisha M.B., Hurvitz H., RA Weingarten G., Chechik E., Fleisher Sheffer V., Haj Yahya R., Meidan G., RA Gross-Kieselstein E., Bauman D., Hershkovitz S., Yaron Y., Orr-Urtreger A., RA Wertheimer E.; RT "Two novel mutations identified in familial cases with Donohue syndrome."; RL Mol. Genet. Genomic Med. 2:64-72(2014). RN [127] RP VARIANTS RMS CYS-256; LEU-635; ILE-835; VAL-842; LEU-874; SER-878 AND RP 999-TYR--SER-1382 DEL, VARIANTS IRAN TYPE A ASP-489 AND MET-1054, VARIANTS RP LEPRCH PHE-657; ARG-659 AND CYS-818, CHARACTERIZATION OF VARIANTS LEPRCH RP PHE-657; ARG-659; CYS-818; THR-925; TRP-926 AND MET-937, AND RP CHARACTERIZATION OF VARIANTS RMS LEU-635; ILE-835; VAL-842; LEU-874 AND RP SER-878. RX PubMed=28765322; DOI=10.2337/db17-0301; RA Hosoe J., Kadowaki H., Miya F., Aizu K., Kawamura T., Miyata I., RA Satomura K., Ito T., Hara K., Tanaka M., Ishiura H., Tsuji S., Suzuki K., RA Takakura M., Boroevich K.A., Tsunoda T., Yamauchi T., Shojima N., RA Kadowaki T.; RT "Structural Basis and Genotype-Phenotype Correlations of INSR Mutations RT Causing Severe Insulin Resistance."; RL Diabetes 66:2713-2723(2017). CC -!- FUNCTION: Receptor tyrosine kinase which mediates the pleiotropic CC actions of insulin. Binding of insulin leads to phosphorylation of CC several intracellular substrates, including, insulin receptor CC substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling CC intermediates. Each of these phosphorylated proteins serve as docking CC proteins for other signaling proteins that contain Src-homology-2 CC domains (SH2 domain) that specifically recognize different CC phosphotyrosine residues, including the p85 regulatory subunit of PI3K CC and SHP2. Phosphorylation of IRSs proteins lead to the activation of CC two main signaling pathways: the PI3K-AKT/PKB pathway, which is CC responsible for most of the metabolic actions of insulin, and the Ras- CC MAPK pathway, which regulates expression of some genes and cooperates CC with the PI3K pathway to control cell growth and differentiation. CC Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to CC the activation of PI3K and the generation of phosphatidylinositol-(3, CC 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates CC several PIP3-dependent serine/threonine kinases, such as PDPK1 and CC subsequently AKT/PKB. The net effect of this pathway is to produce a CC translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic CC vesicles to the cell membrane to facilitate glucose transport. CC Moreover, upon insulin stimulation, activated AKT/PKB is responsible CC for: anti-apoptotic effect of insulin by inducing phosphorylation of CC BAD; regulates the expression of gluconeogenic and lipogenic enzymes by CC controlling the activity of the winged helix or forkhead (FOX) class of CC transcription factors. Another pathway regulated by PI3K-AKT/PKB CC activation is mTORC1 signaling pathway which regulates cell growth and CC metabolism and integrates signals from insulin. AKT mediates insulin- CC stimulated protein synthesis by phosphorylating TSC2 thereby activating CC mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in CC mediating cell growth, survival and cellular differentiation of CC insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers CC the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to CC binding insulin, the insulin receptor can bind insulin-like growth CC factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII CC binding. When present in a hybrid receptor with IGF1R, binds IGF1. CC PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR CC isoform Long are activated with a high affinity by IGF1, with low CC affinity by IGF2 and not significantly activated by insulin, and that CC hybrid receptors composed of IGF1R and INSR isoform Short are activated CC by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that CC hybrid receptors composed of IGF1R and INSR isoform Long and hybrid CC receptors composed of IGF1R and INSR isoform Short have similar binding CC characteristics, both bind IGF1 and have a low affinity for insulin. In CC adipocytes, inhibits lipolysis (By similarity). CC {ECO:0000250|UniProtKB:P15208, ECO:0000269|PubMed:12138094, CC ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16831875, CC ECO:0000269|PubMed:8257688, ECO:0000269|PubMed:8276809, CC ECO:0000269|PubMed:8452530, ECO:0000269|PubMed:9428692}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, CC ECO:0000269|PubMed:11124964, ECO:0000269|PubMed:11598120, CC ECO:0000269|PubMed:12707268, ECO:0000269|PubMed:18278056, CC ECO:0000269|PubMed:19056263, ECO:0000269|PubMed:19071018, CC ECO:0000269|PubMed:19394223, ECO:0000269|PubMed:9312016}; CC -!- ACTIVITY REGULATION: Activated in response to insulin. CC Autophosphorylation activates the kinase activity. PTPN1, PTPRE and CC PTPRF dephosphorylate important tyrosine residues, thereby reducing CC INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the CC catalytic activity of the INSR, they block access of substrates to the CC activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR CC activity, they bind to the activated INRS and interfere with the CC phosphorylation of INSR substrates. {ECO:0000269|PubMed:10615944, CC ECO:0000269|PubMed:11598120, ECO:0000269|PubMed:11726652, CC ECO:0000269|PubMed:12493740, ECO:0000269|PubMed:2211730}. CC -!- SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide CC bonds. The alpha chains carry the insulin-binding regions, while the CC beta chains carry the kinase domain. Forms a hybrid receptor with CC IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta CC chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts CC with SORBS1 but dissociates from it following insulin stimulation. CC Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the CC PTB/PID domains of IRS1 and SHC1. The sequences surrounding the CC phosphorylated NPXY motif contribute differentially to either IRS1 or CC SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2 CC (via PTB domain and 591-786 AA); the 591-786 would be the primary CC anchor of IRS2 to INSR while the PTB domain would have a stabilizing CC action on the interaction with INSR. Interacts with the SH2 domains of CC the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when CC autophosphorylated on tyrosine residues. Interacts with SOCS7. CC Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via CC the phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts CC with CAV2 (tyrosine-phosphorylated form); the interaction is increased CC with 'Tyr-27'phosphorylation of CAV2 (By similarity). Interacts with CC ARRB2 (By similarity). Interacts with GRB10; this interaction blocks CC the association between IRS1/IRS2 and INSR, significantly reduces CC insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus CC decreases insulin signaling. Interacts with GRB7. Interacts with PDPK1. CC Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction CC protects the tyrosines in the activation loop from dephosphorylation, CC but promotes dephosphorylation of Tyr-999, this results in decreased CC interaction with, and phosphorylation of, IRS1. Interacts (via subunit CC alpha) with ENPP1 (via 485-599 AA); this interaction blocks CC autophosphorylation. Interacts with PTPRE; this interaction is CC dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts CC with STAT5B (via SH2 domain). Interacts with PTPRF. Interacts with CC ATIC; ATIC together with PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to CC be part of a signaling netwok regulating INSR autophosphorylation and CC endocytosis (By similarity). Interacts with the cone snail venom CC insulin Con-Ins G1 (PubMed:27617429). Interacts with the insulin CC receptor SORL1; this interaction strongly increases its surface CC exposure, hence strengthens insulin signal reception (PubMed:27322061). CC Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like CC region); binding requires autophosphorylation of the INSR C-terminal CC region (PubMed:25187647). Interacts with GNAI3; the interaction is CC probably mediated by CCDC88A/GIV (PubMed:25187647). Interacts with CC LMBRD1 (By similarity). Interacts (in response to insulin stimulation) CC with NCK1; this interaction may recruit PTPN1 to mediate INSR CC dephosphorylation (PubMed:21707536). {ECO:0000250, CC ECO:0000250|UniProtKB:P15127, ECO:0000250|UniProtKB:P15208, CC ECO:0000269|PubMed:10615944, ECO:0000269|PubMed:10803466, CC ECO:0000269|PubMed:11124964, ECO:0000269|PubMed:11374898, CC ECO:0000269|PubMed:11726652, ECO:0000269|PubMed:12493740, CC ECO:0000269|PubMed:14690593, ECO:0000269|PubMed:16127460, CC ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:16271887, CC ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16957736, CC ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:18767165, CC ECO:0000269|PubMed:19056263, ECO:0000269|PubMed:19071018, CC ECO:0000269|PubMed:19394223, ECO:0000269|PubMed:21707536, CC ECO:0000269|PubMed:2211730, ECO:0000269|PubMed:23302862, CC ECO:0000269|PubMed:25187647, ECO:0000269|PubMed:27322061, CC ECO:0000269|PubMed:27617429, ECO:0000269|PubMed:7537849, CC ECO:0000269|PubMed:7559478, ECO:0000269|PubMed:8276809, CC ECO:0000269|PubMed:8995282, ECO:0000269|PubMed:8999839, CC ECO:0000269|PubMed:9312016, ECO:0000269|PubMed:9428692}. CC -!- INTERACTION: CC P06213; Q99490: AGAP2; NbExp=2; IntAct=EBI-475899, EBI-2361824; CC P06213; Q8NEJ0: DUSP18; NbExp=2; IntAct=EBI-475899, EBI-10698945; CC P06213; Q13322: GRB10; NbExp=3; IntAct=EBI-475899, EBI-80275; CC P06213; P05019: IGF1; NbExp=4; IntAct=EBI-475899, EBI-7902275; CC P06213; P08069: IGF1R; NbExp=5; IntAct=EBI-475899, EBI-475981; CC P06213; P14616: INSRR; NbExp=4; IntAct=EBI-475899, EBI-6424336; CC P06213; P35568: IRS1; NbExp=3; IntAct=EBI-475899, EBI-517592; CC P06213; Q15323: KRT31; NbExp=3; IntAct=EBI-475899, EBI-948001; CC P06213; P27986: PIK3R1; NbExp=5; IntAct=EBI-475899, EBI-79464; CC P06213; P19174: PLCG1; NbExp=9; IntAct=EBI-475899, EBI-79387; CC P06213; P18031: PTPN1; NbExp=33; IntAct=EBI-475899, EBI-968788; CC P06213; Q06124: PTPN11; NbExp=3; IntAct=EBI-475899, EBI-297779; CC P06213; Q15256: PTPRR; NbExp=2; IntAct=EBI-475899, EBI-2265659; CC P06213; Q9NRF2: SH2B1; NbExp=6; IntAct=EBI-475899, EBI-310491; CC P06213; P29353: SHC1; NbExp=2; IntAct=EBI-475899, EBI-78835; CC P06213; P01317: INS; Xeno; NbExp=5; IntAct=EBI-475899, EBI-3989070; CC P06213; P35570: Irs1; Xeno; NbExp=5; IntAct=EBI-475899, EBI-520230; CC P06213-1; P32121: ARRB2; NbExp=2; IntAct=EBI-15558981, EBI-714559; CC P06213-1; P06213-1: INSR; NbExp=4; IntAct=EBI-15558981, EBI-15558981; CC P06213-1; P18031: PTPN1; NbExp=2; IntAct=EBI-15558981, EBI-968788; CC P06213-1; Q92485-2: SMPDL3B; NbExp=2; IntAct=EBI-15558981, EBI-21501656; CC P06213-1; P81122: Irs2; Xeno; NbExp=8; IntAct=EBI-15558981, EBI-1369862; CC P06213-1; Q1XH17: Trim72; Xeno; NbExp=2; IntAct=EBI-15558981, EBI-16034016; CC P06213-2; P01308: INS; NbExp=6; IntAct=EBI-9984921, EBI-7090529; CC P06213-2; Q13257: MAD2L1; NbExp=3; IntAct=EBI-9984921, EBI-78203; CC P06213-2; Q92485-2: SMPDL3B; NbExp=2; IntAct=EBI-9984921, EBI-21501656; CC P06213-2; P01317: INS; Xeno; NbExp=2; IntAct=EBI-9984921, EBI-3989070; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P15208}; CC Single-pass type I membrane protein {ECO:0000305}. Late endosome CC {ECO:0000250|UniProtKB:P15208}. Lysosome CC {ECO:0000250|UniProtKB:P15208}. Note=Binding of insulin to INSR induces CC internalization and lysosomal degradation of the receptor, a means for CC down-regulating this signaling pathway after stimulation. In the CC presence of SORL1, internalized INSR molecules are redirected back to CC the cell surface, thereby preventing their lysosomal catabolism and CC strengthening insulin signal reception. {ECO:0000250|UniProtKB:P15208}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=Long; Synonyms=HIR-B; CC IsoId=P06213-1; Sequence=Displayed; CC Name=Short; Synonyms=HIR-A; CC IsoId=P06213-2; Sequence=VSP_002898; CC -!- TISSUE SPECIFICITY: Isoform Long and isoform Short are predominantly CC expressed in tissue targets of insulin metabolic effects: liver, CC adipose tissue and skeletal muscle but are also expressed in the CC peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta CC vascular endothelium, fibroblasts, monocytes, granulocytes, CC erythrocytes and skin. Isoform Short is preferentially expressed in CC fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found CC as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose CC tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at CC protein level). Overexpressed in several tumors, including breast, CC colon, lung, ovary, and thyroid carcinomas. CC {ECO:0000269|PubMed:10207053, ECO:0000269|PubMed:2369896, CC ECO:0000269|PubMed:9202395, ECO:0000269|PubMed:9355755}. CC -!- DOMAIN: The tetrameric insulin receptor binds insulin via non-identical CC regions from two alpha chains, primarily via the C-terminal region of CC the first INSR alpha chain. Residues from the leucine-rich N-terminus CC of the other INSR alpha chain also contribute to this insulin binding CC site. A secondary insulin-binding site is formed by residues at the CC junction of fibronectin type-III domain 1 and 2. CC {ECO:0000269|PubMed:16957736, ECO:0000269|PubMed:19459609, CC ECO:0000269|PubMed:23302862}. CC -!- PTM: After being transported from the endoplasmic reticulum to the CC Golgi apparatus, the single glycosylated precursor is further CC glycosylated and then cleaved, followed by its transport to the plasma CC membrane. {ECO:0000269|PubMed:1472036, ECO:0000269|PubMed:16894147, CC ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19349973, CC ECO:0000269|PubMed:23302862, ECO:0000269|PubMed:2983222}. CC -!- PTM: Autophosphorylated on tyrosine residues in response to insulin. CC Phosphorylation of Tyr-999 is required for binding to IRS1, SHC1 and CC STAT5B. Dephosphorylated by PTPRE at Tyr-999, Tyr-1185, Tyr-1189 and CC Tyr-1190. Dephosphorylated by PTPRF and PTPN1. Dephosphorylated by CC PTPN2; down-regulates insulin-induced signaling. Dephosphorylation at CC Tyr-1189 and Tyr-1190 requires the SH2/SH3 adapter protein NCK1, CC probably to recruit its interaction partner PTPN1 (PubMed:21707536). CC {ECO:0000269|PubMed:10734133, ECO:0000269|PubMed:12612081, CC ECO:0000269|PubMed:14690593, ECO:0000269|PubMed:16246733, CC ECO:0000269|PubMed:16271887, ECO:0000269|PubMed:18278056, CC ECO:0000269|PubMed:18767165, ECO:0000269|PubMed:21707536, CC ECO:0000269|PubMed:3166375, ECO:0000269|PubMed:9312016}. CC -!- DISEASE: Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin CC resistance syndrome characterized by insulin-resistant diabetes CC mellitus with pineal hyperplasia and somatic abnormalities. Typical CC features include coarse, senile-appearing facies, dental and skin CC abnormalities, abdominal distension, and phallic enlargement. CC Inheritance is autosomal recessive. {ECO:0000269|PubMed:10443650, CC ECO:0000269|PubMed:12023989, ECO:0000269|PubMed:17201797, CC ECO:0000269|PubMed:2121734, ECO:0000269|PubMed:2365819, CC ECO:0000269|PubMed:28765322, ECO:0000269|PubMed:8314008}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Leprechaunism (LEPRCH) [MIM:246200]: Represents the most CC severe form of insulin resistance syndrome, characterized by CC intrauterine and postnatal growth retardation and death in early CC infancy. Inheritance is autosomal recessive. CC {ECO:0000269|PubMed:12023989, ECO:0000269|PubMed:12538626, CC ECO:0000269|PubMed:12970295, ECO:0000269|PubMed:1607067, CC ECO:0000269|PubMed:1730625, ECO:0000269|PubMed:22768670, CC ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:24498630, CC ECO:0000269|PubMed:2479553, ECO:0000269|PubMed:2834824, CC ECO:0000269|PubMed:28765322, ECO:0000269|PubMed:7538143, CC ECO:0000269|PubMed:7815442, ECO:0000269|PubMed:8188715, CC ECO:0000269|PubMed:8326490, ECO:0000269|PubMed:8419945, CC ECO:0000269|PubMed:8636294, ECO:0000269|PubMed:9249867, CC ECO:0000269|PubMed:9299395, ECO:0000269|PubMed:9703342}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Type 2 diabetes mellitus (T2D) [MIM:125853]: A multifactorial CC disorder of glucose homeostasis caused by a lack of sensitivity to the CC body's own insulin. Affected individuals usually have an obese body CC habitus and manifestations of a metabolic syndrome characterized by CC diabetes, insulin resistance, hypertension and hypertriglyceridemia. CC The disease results in long-term complications that affect the eyes, CC kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:1470163, CC ECO:0000269|PubMed:1607076, ECO:0000269|PubMed:7657032}. Note=The gene CC represented in this entry may be involved in disease pathogenesis. CC -!- DISEASE: Hyperinsulinemic hypoglycemia, familial, 5 (HHF5) CC [MIM:609968]: A form of hyperinsulinemic hypoglycemia, a clinically and CC genetically heterogeneous disorder characterized by inappropriate CC insulin secretion from the pancreatic beta-cells in the presence of low CC blood glucose levels. HHF5 clinical features include loss of CC consciousness due to hypoglycemia and hypoglycemic seizures. HHF5 CC inheritance is autosomal dominant. {ECO:0000269|PubMed:15161766}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Insulin-resistant diabetes mellitus with acanthosis nigricans CC type A (IRAN type A) [MIM:610549]: Characterized by the association of CC severe insulin resistance (manifested by marked hyperinsulinemia and a CC failure to respond to exogenous insulin) with the skin lesion CC acanthosis nigricans and ovarian hyperandrogenism in adolescent female CC subjects. Women frequently present with hirsutism, acne, amenorrhea or CC oligomenorrhea, and virilization. This syndrome is different from the CC type B that has been demonstrated to be secondary to the presence of CC circulating autoantibodies against the insulin receptor. CC {ECO:0000269|PubMed:10733238, ECO:0000269|PubMed:11260230, CC ECO:0000269|PubMed:12107746, ECO:0000269|PubMed:12970295, CC ECO:0000269|PubMed:1563582, ECO:0000269|PubMed:1963473, CC ECO:0000269|PubMed:2002058, ECO:0000269|PubMed:2168397, CC ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2544998, CC ECO:0000269|PubMed:28765322, ECO:0000269|PubMed:3283938, CC ECO:0000269|PubMed:8243830, ECO:0000269|PubMed:8288049, CC ECO:0000269|PubMed:8314008, ECO:0000269|PubMed:8388389, CC ECO:0000269|PubMed:9175790}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE- CC ProRule:PRU00159}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Insulin receptor entry; CC URL="https://en.wikipedia.org/wiki/Insulin_receptor"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M10051; AAA59174.1; -; mRNA. DR EMBL; X02160; CAA26096.1; -; mRNA. DR EMBL; M32972; AAA59452.1; -; Genomic_DNA. DR EMBL; M23100; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32823; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32824; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32825; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32826; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32827; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32828; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32829; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32830; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32831; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32832; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32833; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32834; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32835; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32836; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32837; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32838; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32839; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32840; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32841; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; M32842; AAA59452.1; JOINED; Genomic_DNA. DR EMBL; AC010311; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC010526; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC010606; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC125387; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC117172; AAI17173.1; -; mRNA. DR EMBL; J03466; AAA59175.1; -; Genomic_DNA. DR EMBL; J05043; AAA59190.1; -; Genomic_DNA. DR EMBL; M76592; AAC37604.1; -; Genomic_DNA. DR EMBL; AB208861; BAD92098.1; -; mRNA. DR EMBL; M24555; AAA59178.1; -; mRNA. DR EMBL; M29929; AAA59176.1; -; Genomic_DNA. DR EMBL; M29930; AAA59177.1; -; Genomic_DNA. DR EMBL; M27197; AAA86791.1; -; Genomic_DNA. DR EMBL; M27195; AAA86791.1; JOINED; Genomic_DNA. DR CCDS; CCDS12176.1; -. [P06213-1] DR CCDS; CCDS42487.1; -. [P06213-2] DR PIR; A37348; INHUR. DR RefSeq; NP_000199.2; NM_000208.3. [P06213-1] DR RefSeq; NP_001073285.1; NM_001079817.2. [P06213-2] DR PDB; 1GAG; X-ray; 2.70 A; A=1005-1310. DR PDB; 1I44; X-ray; 2.40 A; A=1005-1310. DR PDB; 1IR3; X-ray; 1.90 A; A=1005-1310. DR PDB; 1IRK; X-ray; 2.10 A; A=1005-1310. DR PDB; 1P14; X-ray; 1.90 A; A=1005-1310. DR PDB; 1RQQ; X-ray; 2.60 A; A/B=1005-1310. DR PDB; 2AUH; X-ray; 3.20 A; A=1005-1310. DR PDB; 2B4S; X-ray; 2.30 A; B/D=1005-1310. DR PDB; 2HR7; X-ray; 2.32 A; A/B=28-512. DR PDB; 2MFR; NMR; -; A=940-988. DR PDB; 2Z8C; X-ray; 3.25 A; A=1008-1310. DR PDB; 3BU3; X-ray; 1.65 A; A=1005-1310. DR PDB; 3BU5; X-ray; 2.10 A; A=1005-1310. DR PDB; 3BU6; X-ray; 1.95 A; A=1005-1310. DR PDB; 3EKK; X-ray; 2.10 A; A=1005-1310. DR PDB; 3EKN; X-ray; 2.20 A; A=1005-1310. DR PDB; 3ETA; X-ray; 2.60 A; A/B=1017-1322. DR PDB; 3W11; X-ray; 3.90 A; E=28-337, F=731-744. DR PDB; 3W12; X-ray; 4.30 A; E=28-337, F=731-744. DR PDB; 3W13; X-ray; 4.30 A; E=28-337, F=724-744. DR PDB; 4IBM; X-ray; 1.80 A; A/B=1005-1310. DR PDB; 4OGA; X-ray; 3.50 A; E=28-337, F=731-744. DR PDB; 4XLV; X-ray; 2.30 A; A=983-1310. DR PDB; 4XSS; X-ray; 3.00 A; E=28-337. DR PDB; 4XST; X-ray; 3.00 A; E=28-337. DR PDB; 4ZXB; X-ray; 3.30 A; E=28-956. DR PDB; 5E1S; X-ray; 2.26 A; A=1005-1310. DR PDB; 5HHW; X-ray; 1.79 A; A=1005-1310. DR PDB; 5J3H; X-ray; 3.27 A; E=28-337. DR PDB; 5KQV; X-ray; 4.40 A; E/F=28-746. DR PDB; 5U1M; X-ray; 1.80 A; B=991-999. DR PDB; 6HN4; EM; 4.20 A; E/F=28-955. DR PDB; 6HN5; EM; 3.20 A; E/F=28-955. DR PDB; 6PXV; EM; 3.20 A; A/C=28-1382. DR PDB; 6PXW; EM; 3.10 A; A/B=28-1382. DR PDB; 6SOF; EM; 4.30 A; A/C=28-746, B/D=795-956. DR PDB; 6VEP; X-ray; 2.90 A; E/K/Q/W=28-337, F/L/R/X=731-746. DR PDB; 6VEQ; X-ray; 3.25 A; E/K=28-337, F/L=731-746. DR PDB; 7BW7; EM; 4.10 A; A/C=28-1382. DR PDB; 7BW8; EM; 3.80 A; A/C=28-1382. DR PDB; 7BWA; EM; 4.90 A; A/C=28-1382. DR PDB; 7KD6; X-ray; 2.60 A; E/K/Q/W=28-337. DR PDB; 7MQO; EM; 3.40 A; E/F=28-956. DR PDB; 7MQR; EM; 4.10 A; E/F=28-955. DR PDB; 7MQS; EM; 4.40 A; E/F=28-955. DR PDB; 7PG0; EM; 7.60 A; A/B=1-1382. DR PDB; 7PG2; EM; 6.70 A; A/B=1-1382. DR PDB; 7PG3; EM; 7.30 A; A/B=1-1382. DR PDB; 7PG4; EM; 9.10 A; A/B=1-1382. DR PDB; 7PHT; NMR; -; A=953-982. DR PDB; 7QID; EM; 5.00 A; A/C=28-746, B/D=763-956. DR PDB; 7S0Q; EM; 3.70 A; B=28-955. DR PDB; 7S8V; EM; 3.73 A; B=28-955. DR PDB; 7U6D; EM; 5.03 A; B/C=28-955. DR PDB; 7U6E; EM; 3.00 A; E/F=28-955. DR PDB; 7YQ3; EM; 3.60 A; E/F=28-946. DR PDB; 7YQ4; EM; 3.95 A; E/F=28-946. DR PDB; 7YQ5; EM; 4.27 A; E/F=28-946. DR PDB; 7YQ6; EM; 4.18 A; E/F=28-946. DR PDB; 8DWN; X-ray; 2.15 A; A=1005-1310. DR PDB; 8GUY; EM; 4.18 A; E/F=28-946. DR PDBsum; 1GAG; -. DR PDBsum; 1I44; -. DR PDBsum; 1IR3; -. DR PDBsum; 1IRK; -. DR PDBsum; 1P14; -. DR PDBsum; 1RQQ; -. DR PDBsum; 2AUH; -. DR PDBsum; 2B4S; -. DR PDBsum; 2HR7; -. DR PDBsum; 2MFR; -. DR PDBsum; 2Z8C; -. DR PDBsum; 3BU3; -. DR PDBsum; 3BU5; -. DR PDBsum; 3BU6; -. DR PDBsum; 3EKK; -. DR PDBsum; 3EKN; -. DR PDBsum; 3ETA; -. DR PDBsum; 3W11; -. DR PDBsum; 3W12; -. DR PDBsum; 3W13; -. DR PDBsum; 4IBM; -. DR PDBsum; 4OGA; -. DR PDBsum; 4XLV; -. DR PDBsum; 4XSS; -. DR PDBsum; 4XST; -. DR PDBsum; 4ZXB; -. DR PDBsum; 5E1S; -. DR PDBsum; 5HHW; -. DR PDBsum; 5J3H; -. DR PDBsum; 5KQV; -. DR PDBsum; 5U1M; -. DR PDBsum; 6HN4; -. DR PDBsum; 6HN5; -. DR PDBsum; 6PXV; -. DR PDBsum; 6PXW; -. DR PDBsum; 6SOF; -. DR PDBsum; 6VEP; -. DR PDBsum; 6VEQ; -. DR PDBsum; 7BW7; -. DR PDBsum; 7BW8; -. DR PDBsum; 7BWA; -. DR PDBsum; 7KD6; -. DR PDBsum; 7MQO; -. DR PDBsum; 7MQR; -. DR PDBsum; 7MQS; -. DR PDBsum; 7PG0; -. DR PDBsum; 7PG2; -. DR PDBsum; 7PG3; -. DR PDBsum; 7PG4; -. DR PDBsum; 7PHT; -. DR PDBsum; 7QID; -. DR PDBsum; 7S0Q; -. DR PDBsum; 7S8V; -. DR PDBsum; 7U6D; -. DR PDBsum; 7U6E; -. DR PDBsum; 7YQ3; -. DR PDBsum; 7YQ4; -. DR PDBsum; 7YQ5; -. DR PDBsum; 7YQ6; -. DR PDBsum; 8DWN; -. DR PDBsum; 8GUY; -. DR AlphaFoldDB; P06213; -. DR BMRB; P06213; -. DR EMDB; EMD-10273; -. DR EMDB; EMD-10311; -. DR EMDB; EMD-13385; -. DR EMDB; EMD-13386; -. DR EMDB; EMD-13387; -. DR EMDB; EMD-13388; -. DR EMDB; EMD-20522; -. DR EMDB; EMD-20523; -. DR EMDB; EMD-23766; -. DR EMDB; EMD-23767; -. DR EMDB; EMD-23949; -. DR EMDB; EMD-23950; -. DR EMDB; EMD-23951; -. DR EMDB; EMD-24791; -. DR EMDB; EMD-24927; -. DR EMDB; EMD-26363; -. DR EMDB; EMD-26364; -. DR EMDB; EMD-30225; -. DR EMDB; EMD-30227; -. DR EMDB; EMD-30229; -. DR EMDB; EMD-30230; -. DR EMDB; EMD-30231; -. DR EMDB; EMD-34018; -. DR EMDB; EMD-34019; -. DR EMDB; EMD-34020; -. DR EMDB; EMD-34021; -. DR EMDB; EMD-34281; -. DR EMDB; EMD-7461; -. DR EMDB; EMD-7462; -. DR EMDB; EMD-7463; -. DR SASBDB; P06213; -. DR SMR; P06213; -. DR BioGRID; 109854; 360. DR CORUM; P06213; -. DR DIP; DIP-480N; -. DR ELM; P06213; -. DR IntAct; P06213; 247. DR MINT; P06213; -. DR STRING; 9606.ENSP00000303830; -. DR BindingDB; P06213; -. DR ChEMBL; CHEMBL1981; -. DR DrugBank; DB08513; [4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID. DR DrugBank; DB03909; Adenosine-5'-[Beta, Gamma-Methylene]Triphosphate. DR DrugBank; DB05120; AT1391. DR DrugBank; DB15399; BMS-754807. DR DrugBank; DB12267; Brigatinib. DR DrugBank; DB09129; Chromic chloride. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB11564; Insulin argine. DR DrugBank; DB01306; Insulin aspart. DR DrugBank; DB09456; Insulin beef. DR DrugBank; DB09564; Insulin degludec. DR DrugBank; DB01307; Insulin detemir. DR DrugBank; DB00047; Insulin glargine. DR DrugBank; DB01309; Insulin glulisine. DR DrugBank; DB00030; Insulin human. DR DrugBank; DB00046; Insulin lispro. DR DrugBank; DB11567; Insulin peglispro. DR DrugBank; DB00071; Insulin pork. DR DrugBank; DB11568; Insulin tregopil. DR DrugBank; DB16637; KW-2450 free base. DR DrugBank; DB06075; Linsitinib. DR DrugBank; DB01277; Mecasermin. DR DrugBank; DB14751; Mecasermin rinfabate. DR DrugBank; DB05115; NN344. DR DrugCentral; P06213; -. DR GuidetoPHARMACOLOGY; 1800; -. DR GlyConnect; 1402; 8 N-Linked glycans (6 sites). DR GlyCosmos; P06213; 21 sites, 11 glycans. DR GlyGen; P06213; 22 sites, 8 N-linked glycans (6 sites), 4 O-linked glycans (4 sites). DR iPTMnet; P06213; -. DR PhosphoSitePlus; P06213; -. DR SwissPalm; P06213; -. DR BioMuta; INSR; -. DR DMDM; 308153655; -. DR CPTAC; CPTAC-1771; -. DR CPTAC; CPTAC-1772; -. DR CPTAC; CPTAC-2814; -. DR CPTAC; CPTAC-3053; -. DR EPD; P06213; -. DR jPOST; P06213; -. DR MassIVE; P06213; -. DR MaxQB; P06213; -. DR PaxDb; 9606-ENSP00000303830; -. DR PeptideAtlas; P06213; -. DR ProteomicsDB; 51872; -. [P06213-1] DR ProteomicsDB; 51873; -. [P06213-2] DR Pumba; P06213; -. DR ABCD; P06213; 3 sequenced antibodies. DR Antibodypedia; 3403; 2541 antibodies from 53 providers. DR DNASU; 3643; -. DR Ensembl; ENST00000302850.10; ENSP00000303830.4; ENSG00000171105.14. [P06213-1] DR Ensembl; ENST00000341500.9; ENSP00000342838.4; ENSG00000171105.14. [P06213-2] DR GeneID; 3643; -. DR KEGG; hsa:3643; -. DR MANE-Select; ENST00000302850.10; ENSP00000303830.4; NM_000208.4; NP_000199.2. DR UCSC; uc002mgd.2; human. [P06213-1] DR AGR; HGNC:6091; -. DR CTD; 3643; -. DR DisGeNET; 3643; -. DR GeneCards; INSR; -. DR GeneReviews; INSR; -. DR HGNC; HGNC:6091; INSR. DR HPA; ENSG00000171105; Low tissue specificity. DR MalaCards; INSR; -. DR MIM; 125853; phenotype. DR MIM; 147670; gene. DR MIM; 246200; phenotype. DR MIM; 262190; phenotype. DR MIM; 609968; phenotype. DR MIM; 610549; phenotype. DR neXtProt; NX_P06213; -. DR OpenTargets; ENSG00000171105; -. DR Orphanet; 263458; Hyperinsulinism due to INSR deficiency. DR Orphanet; 2297; Insulin-resistance syndrome type A. DR Orphanet; 508; Leprechaunism. DR Orphanet; 769; Rabson-Mendenhall syndrome. DR PharmGKB; PA202; -. DR VEuPathDB; HostDB:ENSG00000171105; -. DR eggNOG; KOG4258; Eukaryota. DR GeneTree; ENSGT00940000155404; -. DR HOGENOM; CLU_000288_166_0_1; -. DR InParanoid; P06213; -. DR OMA; VCITRRD; -. DR OrthoDB; 1614410at2759; -. DR PhylomeDB; P06213; -. DR TreeFam; TF351636; -. DR BRENDA; 2.7.10.1; 2681. DR PathwayCommons; P06213; -. DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR Reactome; R-HSA-74713; IRS activation. DR Reactome; R-HSA-74749; Signal attenuation. DR Reactome; R-HSA-74751; Insulin receptor signalling cascade. DR Reactome; R-HSA-74752; Signaling by Insulin receptor. DR Reactome; R-HSA-77387; Insulin receptor recycling. DR SABIO-RK; P06213; -. DR SignaLink; P06213; -. DR SIGNOR; P06213; -. DR BioGRID-ORCS; 3643; 15 hits in 1203 CRISPR screens. DR ChiTaRS; INSR; human. DR EvolutionaryTrace; P06213; -. DR GeneWiki; Insulin_receptor; -. DR GenomeRNAi; 3643; -. DR Pharos; P06213; Tclin. DR PRO; PR:P06213; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P06213; Protein. DR Bgee; ENSG00000171105; Expressed in buccal mucosa cell and 209 other cell types or tissues. DR ExpressionAtlas; P06213; baseline and differential. DR Genevisible; P06213; HS. DR GO; GO:0030424; C:axon; IBA:GO_Central. DR GO; GO:0005901; C:caveola; IDA:BHF-UCL. DR GO; GO:0032590; C:dendrite membrane; ISS:ARUK-UCL. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0009897; C:external side of plasma membrane; ISS:ARUK-UCL. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005899; C:insulin receptor complex; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell. DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IDA:BHF-UCL. DR GO; GO:0032809; C:neuronal cell body membrane; ISS:ARUK-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL. DR GO; GO:0043235; C:receptor complex; IDA:MGI. DR GO; GO:0001540; F:amyloid-beta binding; IPI:ARUK-UCL. DR GO; GO:0005524; F:ATP binding; IDA:BHF-UCL. DR GO; GO:0038024; F:cargo receptor activity; ISS:ARUK-UCL. DR GO; GO:0005525; F:GTP binding; IDA:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0043559; F:insulin binding; IDA:UniProtKB. DR GO; GO:0005009; F:insulin receptor activity; IDA:UniProtKB. DR GO; GO:0043560; F:insulin receptor substrate binding; IPI:UniProtKB. DR GO; GO:0031994; F:insulin-like growth factor I binding; IPI:BHF-UCL. DR GO; GO:0031995; F:insulin-like growth factor II binding; IPI:BHF-UCL. DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IDA:BHF-UCL. DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IPI:UniProtKB. DR GO; GO:0019904; F:protein domain specific binding; IPI:CAFA. DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:BHF-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL. DR GO; GO:0051425; F:PTB domain binding; IPI:UniProtKB. DR GO; GO:0032147; P:activation of protein kinase activity; IMP:BHF-UCL. DR GO; GO:0032148; P:activation of protein kinase B activity; IDA:BHF-UCL. DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl. DR GO; GO:0097242; P:amyloid-beta clearance; ISS:ARUK-UCL. DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:UniProtKB-KW. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl. DR GO; GO:0032869; P:cellular response to insulin stimulus; IDA:BHF-UCL. DR GO; GO:0097062; P:dendritic spine maintenance; ISS:ARUK-UCL. DR GO; GO:0008544; P:epidermis development; IEA:Ensembl. DR GO; GO:0031017; P:exocrine pancreas development; IEA:Ensembl. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0042593; P:glucose homeostasis; IMP:BHF-UCL. DR GO; GO:0003007; P:heart morphogenesis; IMP:BHF-UCL. DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0007612; P:learning; TAS:ARUK-UCL. DR GO; GO:0008584; P:male gonad development; IEA:Ensembl. DR GO; GO:0030238; P:male sex determination; IEA:Ensembl. DR GO; GO:0007613; P:memory; TAS:ARUK-UCL. DR GO; GO:1990535; P:neuron projection maintenance; ISS:ARUK-UCL. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:BHF-UCL. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL. DR GO; GO:0048639; P:positive regulation of developmental growth; IMP:BHF-UCL. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IEA:Ensembl. DR GO; GO:0046326; P:positive regulation of glucose import; IDA:BHF-UCL. DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IDA:BHF-UCL. DR GO; GO:0045821; P:positive regulation of glycolytic process; IMP:BHF-UCL. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IMP:BHF-UCL. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0051446; P:positive regulation of meiotic cell cycle; IEA:Ensembl. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IMP:BHF-UCL. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IMP:BHF-UCL. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:BHF-UCL. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:BHF-UCL. DR GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; ISS:ARUK-UCL. DR GO; GO:0002092; P:positive regulation of receptor internalization; IDA:CACAO. DR GO; GO:0060267; P:positive regulation of respiratory burst; IDA:BHF-UCL. DR GO; GO:0046777; P:protein autophosphorylation; IDA:BHF-UCL. DR GO; GO:0006468; P:protein phosphorylation; TAS:ARUK-UCL. DR GO; GO:0031623; P:receptor internalization; IEA:Ensembl. DR GO; GO:0006898; P:receptor-mediated endocytosis; ISS:ARUK-UCL. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IMP:BHF-UCL. DR GO; GO:0045995; P:regulation of embryonic development; IMP:BHF-UCL. DR GO; GO:2000194; P:regulation of female gonad development; IEA:Ensembl. DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central. DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL. DR GO; GO:0046718; P:viral entry into host cell; IMP:BHF-UCL. DR CDD; cd00063; FN3; 2. DR CDD; cd00064; FU; 1. DR CDD; cd05061; PTKc_InsR; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 4. DR Gene3D; 3.80.20.20; Receptor L-domain; 2. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR006211; Furin-like_Cys-rich_dom. DR InterPro; IPR006212; Furin_repeat. DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR040969; Insulin_TMD. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR000494; Rcpt_L-dom. DR InterPro; IPR036941; Rcpt_L-dom_sf. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR InterPro; IPR016246; Tyr_kinase_insulin-like_rcpt. DR InterPro; IPR002011; Tyr_kinase_rcpt_2_CS. DR PANTHER; PTHR24416:SF535; INSULIN RECEPTOR; 1. DR PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1. DR Pfam; PF00041; fn3; 1. DR Pfam; PF00757; Furin-like; 1. DR Pfam; PF17870; Insulin_TMD; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR Pfam; PF01030; Recep_L_domain; 2. DR PIRSF; PIRSF000620; Insulin_receptor; 1. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00060; FN3; 3. DR SMART; SM00261; FU; 2. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF49265; Fibronectin type III; 3. DR SUPFAM; SSF57184; Growth factor receptor domain; 1. DR SUPFAM; SSF52058; L domain-like; 2. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50853; FN3; 2. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. DR PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Carbohydrate metabolism; KW Cell membrane; Cleavage on pair of basic residues; Diabetes mellitus; KW Direct protein sequencing; Disease variant; Disulfide bond; Endosome; KW Glycoprotein; Kinase; Lysosome; Membrane; Nucleotide-binding; KW Phosphoprotein; Receptor; Reference proteome; Repeat; Signal; Transferase; KW Transmembrane; Transmembrane helix; Tyrosine-protein kinase. FT SIGNAL 1..27 FT /evidence="ECO:0000269|PubMed:2211730, FT ECO:0000269|PubMed:2983222, ECO:0000269|PubMed:8257688" FT CHAIN 28..758 FT /note="Insulin receptor subunit alpha" FT /id="PRO_0000016687" FT CHAIN 763..1382 FT /note="Insulin receptor subunit beta" FT /id="PRO_0000016689" FT TOPO_DOM 28..758 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TOPO_DOM 763..956 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 957..979 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 980..1382 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT DOMAIN 624..726 FT /note="Fibronectin type-III 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 757..842 FT /note="Fibronectin type-III 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 853..947 FT /note="Fibronectin type-III 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1023..1298 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 686..708 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 733..741 FT /note="Insulin-binding" FT REGION 746..766 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 999 FT /note="Important for interaction with IRS1, SHC1 and FT STAT5B" FT /evidence="ECO:0000269|PubMed:9428692" FT REGION 1360..1382 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1361..1364 FT /note="PIK3R1-binding" FT ACT_SITE 1159 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000269|PubMed:9312016" FT BINDING 1033 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000269|PubMed:18278056" FT BINDING 1057 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000269|PubMed:18278056" FT BINDING 1104..1110 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000269|PubMed:18278056" FT BINDING 1163..1164 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000269|PubMed:18278056" FT BINDING 1177 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000269|PubMed:18278056" FT SITE 66 FT /note="Insulin-binding" FT /evidence="ECO:0000305" FT MOD_RES 400 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 401 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 407 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 992 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000305" FT MOD_RES 999 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:3166375" FT MOD_RES 1011 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000305" FT MOD_RES 1185 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:14690593, FT ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:16271887, FT ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:18767165, FT ECO:0000269|PubMed:3166375, ECO:0000269|PubMed:9312016" FT MOD_RES 1189 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:14690593, FT ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:16271887, FT ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:18767165, FT ECO:0000269|PubMed:3166375, ECO:0000269|PubMed:9312016" FT MOD_RES 1190 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:14690593, FT ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:16271887, FT ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:18767165, FT ECO:0000269|PubMed:3166375, ECO:0000269|PubMed:9312016" FT MOD_RES 1355 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:3166375" FT MOD_RES 1361 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:3166375" FT CARBOHYD 43 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16894147, FT ECO:0000269|PubMed:23302862, ECO:0000269|PubMed:2983222" FT CARBOHYD 52 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16894147, FT ECO:0000269|PubMed:23302862" FT CARBOHYD 105 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 138 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16894147, FT ECO:0000269|PubMed:23302862" FT CARBOHYD 242 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16894147, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:23302862" FT CARBOHYD 282 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16894147, FT ECO:0000269|PubMed:23302862" FT CARBOHYD 322 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 364 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16894147" FT CARBOHYD 424 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16894147" FT CARBOHYD 445 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16894147, FT ECO:0000269|PubMed:19349973" FT CARBOHYD 541 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:1472036, FT ECO:0000269|PubMed:19159218" FT CARBOHYD 633 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 651 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 698 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 769 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:2983222" FT CARBOHYD 782 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 920 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT CARBOHYD 933 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 35..53 FT DISULFID 153..182 FT DISULFID 186..209 FT DISULFID 196..215 FT DISULFID 219..228 FT DISULFID 223..234 FT DISULFID 235..243 FT DISULFID 239..252 FT DISULFID 255..264 FT DISULFID 268..280 FT DISULFID 286..311 FT DISULFID 293..301 FT DISULFID 315..328 FT DISULFID 331..335 FT DISULFID 339..360 FT DISULFID 462..495 FT /evidence="ECO:0000269|PubMed:1472036" FT DISULFID 551 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:1472036" FT DISULFID 674..899 FT DISULFID 825..834 FT VAR_SEQ 745..756 FT /note="Missing (in isoform Short)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2983222, ECO:0000303|Ref.13" FT /id="VSP_002898" FT VARIANT 2 FT /note="A -> G (in dbSNP:rs7508518)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:2210055, ECO:0000269|PubMed:2280779, FT ECO:0000269|PubMed:2777789, ECO:0000269|PubMed:2806055, FT ECO:0000269|PubMed:2859121, ECO:0000269|PubMed:2983222, FT ECO:0000269|PubMed:3680248" FT /id="VAR_058395" FT VARIANT 42 FT /note="N -> K (in RMS; impairs transport to the plasma FT membrane and reduces the affinity to bind insulin; FT dbSNP:rs121913143)" FT /evidence="ECO:0000269|PubMed:2121734, FT ECO:0000269|PubMed:2365819" FT /id="VAR_004079" FT VARIANT 55 FT /note="V -> A (in LEPRCH; Verona-1; dbSNP:rs121913152)" FT /evidence="ECO:0000269|PubMed:1607067" FT /id="VAR_004080" FT VARIANT 56 FT /note="I -> T (in LEPRCH; abolishes post-translational FT processing; dbSNP:rs1555689937)" FT /evidence="ECO:0000269|PubMed:24498630" FT /id="VAR_079535" FT VARIANT 58 FT /note="G -> R (in LEPRCH; Helmond; inhibits processing and FT transport; dbSNP:rs52836744)" FT /evidence="ECO:0000269|PubMed:1730625" FT /id="VAR_004081" FT VARIANT 86 FT /note="D -> G (in IRAN type A)" FT /evidence="ECO:0000269|PubMed:9175790" FT /id="VAR_015907" FT VARIANT 89 FT /note="L -> P (in IRAN type A)" FT /evidence="ECO:0000269|PubMed:9175790" FT /id="VAR_015908" FT VARIANT 113 FT /note="R -> P (in LEPRCH; Atlanta-1; abolishes insulin FT binding; dbSNP:rs121913153)" FT /evidence="ECO:0000269|PubMed:12023989, FT ECO:0000269|PubMed:8419945" FT /id="VAR_004082" FT VARIANT 119 FT /note="A -> V (in LEPRCH; markedly impairs insulin binding; FT dbSNP:rs1347473020)" FT /evidence="ECO:0000269|PubMed:12023989" FT /id="VAR_015909" FT VARIANT 120 FT /note="L -> Q (in LEPRCH; inhibits receptor processing)" FT /evidence="ECO:0000269|PubMed:12970295" FT /id="VAR_031518" FT VARIANT 146 FT /note="I -> M (in LEPRCH; mild; dbSNP:rs121913159)" FT /evidence="ECO:0000269|PubMed:7815442, FT ECO:0000269|PubMed:8326490" FT /id="VAR_015539" FT VARIANT 167 FT /note="V -> L (in IRAN type A; dbSNP:rs938519025)" FT /evidence="ECO:0000269|PubMed:10733238" FT /id="VAR_015910" FT VARIANT 171 FT /note="Y -> H (in dbSNP:rs1051692)" FT /evidence="ECO:0000269|PubMed:2859121" FT /id="VAR_058396" FT VARIANT 220 FT /note="P -> L (in Ins resistance; severe; FT dbSNP:rs749094324)" FT /evidence="ECO:0000269|PubMed:8242067" FT /id="VAR_004083" FT VARIANT 228 FT /note="C -> R (in a gastric adenocarcinoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041429" FT VARIANT 236 FT /note="H -> R (in RMS and LEPRCH; Winnipeg; may impair FT receptor processing; dbSNP:rs121913145)" FT /evidence="ECO:0000269|PubMed:17201797, FT ECO:0000269|PubMed:2365819" FT /id="VAR_004084" FT VARIANT 256 FT /note="R -> C (in RMS; dbSNP:rs781007453)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079536" FT VARIANT 260 FT /note="L -> P (in LEPRCH; Geldeimalsen; dbSNP:rs121913141)" FT /evidence="ECO:0000269|PubMed:2479553" FT /id="VAR_004085" FT VARIANT 279 FT /note="R -> C (in IRAN type A; inhibits receptor FT internalization; dbSNP:rs1568470274)" FT /evidence="ECO:0000269|PubMed:12107746" FT /id="VAR_015540" FT VARIANT 279 FT /note="R -> H (in IRAN type A; interferes with receptor FT processing; dbSNP:rs1329693158)" FT /evidence="ECO:0000269|PubMed:12970295" FT /id="VAR_031519" FT VARIANT 280 FT /note="C -> Y (in IRAN type A)" FT /evidence="ECO:0000269|PubMed:11260230" FT /id="VAR_015911" FT VARIANT 286 FT /note="C -> Y (in LEPRCH; abolishes post-translational FT processing)" FT /evidence="ECO:0000269|PubMed:24498630" FT /id="VAR_079537" FT VARIANT 301 FT /note="C -> Y (in LEPRCH)" FT /evidence="ECO:0000269|PubMed:9703342" FT /id="VAR_015912" FT VARIANT 308 FT /note="Missing (in LEPRCH; abolishes insulin binding)" FT /evidence="ECO:0000269|PubMed:12023989, FT ECO:0000269|PubMed:7538143, ECO:0000269|PubMed:8636294" FT /id="VAR_015913" FT VARIANT 350 FT /note="S -> L (in RMS and LEPRCH)" FT /evidence="ECO:0000269|PubMed:12970295, FT ECO:0000269|PubMed:8314008" FT /id="VAR_015914" FT VARIANT 362 FT /note="Missing (in LEPRCH)" FT /evidence="ECO:0000269|PubMed:12538626" FT /id="VAR_015541" FT VARIANT 386 FT /note="G -> S (in RMS; may impair receptor processing; FT dbSNP:rs764221583)" FT /evidence="ECO:0000269|PubMed:17201797" FT /id="VAR_031520" FT VARIANT 393 FT /note="G -> R (in LEPRCH; Verona-1; dbSNP:rs267607184)" FT /evidence="ECO:0000269|PubMed:1607067" FT /id="VAR_004086" FT VARIANT 409 FT /note="F -> V (in IRAN type A; dbSNP:rs121913142)" FT /evidence="ECO:0000269|PubMed:8388389" FT /id="VAR_004087" FT VARIANT 439 FT /note="W -> S (in LEPRCH; impairs transport of the receptor FT to the cell surface; dbSNP:rs121913158)" FT /evidence="ECO:0000269|PubMed:8188715" FT /id="VAR_015542" FT VARIANT 448 FT /note="I -> T (in dbSNP:rs1051691)" FT /evidence="ECO:0000269|PubMed:2859121" FT /id="VAR_015915" FT VARIANT 458 FT /note="N -> D (in LEPRCH; partially inhibits receptor FT processing and autophosphorylation; strongly impairs ERK FT phosphorylation; induces wild-type levels of IRS-1 FT phosphorylation; dbSNP:rs121913160)" FT /evidence="ECO:0000269|PubMed:12970295" FT /id="VAR_031521" FT VARIANT 487 FT /note="K -> E (in LEPRCH; ARK-1; dbSNP:rs121913136)" FT /evidence="ECO:0000269|PubMed:2834824" FT /id="VAR_004088" FT VARIANT 489 FT /note="N -> D (in IRAN type A; uncertain significance; FT dbSNP:rs1135401742)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079538" FT VARIANT 489 FT /note="N -> S (in IRAN type A; dbSNP:rs121913147)" FT /evidence="ECO:0000269|PubMed:2365819" FT /id="VAR_004089" FT VARIANT 492 FT /note="Q -> K" FT /evidence="ECO:0000269|PubMed:2859121" FT /id="VAR_015916" FT VARIANT 635 FT /note="S -> L (in RMS; decreases post-translational FT processing)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079539" FT VARIANT 657 FT /note="V -> F (in LEPRCH; impairs post-translational FT processing; dbSNP:rs1135401737)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079540" FT VARIANT 659 FT /note="W -> R (in LEPRCH; impairs post-translational FT processing)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079541" FT VARIANT 695 FT /note="Q -> R (in dbSNP:rs55906835)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041430" FT VARIANT 762 FT /note="R -> S (in IRAN type A; dbSNP:rs121913138)" FT /evidence="ECO:0000269|PubMed:3283938" FT /id="VAR_004090" FT VARIANT 811 FT /note="G -> S (in dbSNP:rs35045353)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041431" FT VARIANT 818 FT /note="Y -> C (in LEPRCH; abolishes post-translational FT processing)" FT /evidence="ECO:0000269|PubMed:22768670, FT ECO:0000269|PubMed:28765322" FT /id="VAR_079542" FT VARIANT 830 FT /note="P -> L (in dbSNP:rs2162771)" FT /id="VAR_055986" FT VARIANT 835 FT /note="S -> I (in RMS; impairs post-translational FT processing; dbSNP:rs1135401739)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079543" FT VARIANT 842 FT /note="A -> V (in RMS; decreases post-translational FT processing; dbSNP:rs1135401738)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079544" FT VARIANT 858 FT /note="T -> A (in T2D; dbSNP:rs182552223)" FT /evidence="ECO:0000269|PubMed:7657032" FT /id="VAR_015917" FT VARIANT 874 FT /note="P -> L (in RMS; impairs post-translational FT processing)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079545" FT VARIANT 878 FT /note="N -> S (in RMS; impairs post-translational FT processing; dbSNP:rs887190835)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079546" FT VARIANT 890..1382 FT /note="Missing (in LEPRCH)" FT /evidence="ECO:0000269|PubMed:22768670" FT /id="VAR_079547" FT VARIANT 925 FT /note="I -> T (in LEPRCH; abolishes post-translational FT processing; abolishes insulin binding; dbSNP:rs1599881881)" FT /evidence="ECO:0000269|PubMed:12023989, FT ECO:0000269|PubMed:28765322" FT /id="VAR_015918" FT VARIANT 926 FT /note="R -> W (in LEPRCH; markedly impairs insulin FT binding;impairs post-translational processing; FT dbSNP:rs911929963)" FT /evidence="ECO:0000269|PubMed:12023989, FT ECO:0000269|PubMed:28765322" FT /id="VAR_015919" FT VARIANT 937 FT /note="T -> M (in LEPRCH; impaired receptor processing; FT impairs post-translational processing)" FT /evidence="ECO:0000269|PubMed:28765322, FT ECO:0000269|PubMed:9299395" FT /id="VAR_015920" FT VARIANT 997 FT /note="P -> T (in RMS; reduces insulin binding)" FT /evidence="ECO:0000269|PubMed:12023989" FT /id="VAR_015921" FT VARIANT 999..1382 FT /note="Missing (in RMS)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079548" FT VARIANT 1012 FT /note="V -> M (in dbSNP:rs1799816)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:8314008, ECO:0000269|PubMed:8432414, FT ECO:0000269|PubMed:8458533, ECO:0000269|PubMed:9199575" FT /id="VAR_004091" FT VARIANT 1020 FT /note="R -> Q (in IRAN type A; dbSNP:rs121913148)" FT /evidence="ECO:0000269|PubMed:2002058" FT /id="VAR_004092" FT VARIANT 1023 FT /note="I -> F" FT /evidence="ECO:0000269|PubMed:8890729" FT /id="VAR_015922" FT VARIANT 1035 FT /note="G -> V (in IRAN type A; dbSNP:rs121913135)" FT /evidence="ECO:0000269|PubMed:2544998" FT /id="VAR_004093" FT VARIANT 1054 FT /note="V -> M (in IRAN type A; uncertain significance; FT dbSNP:rs1135401741)" FT /evidence="ECO:0000269|PubMed:28765322" FT /id="VAR_079549" FT VARIANT 1055 FT /note="A -> V (in IRAN type A; dbSNP:rs1599874183)" FT /evidence="ECO:0000269|PubMed:10733238" FT /id="VAR_015923" FT VARIANT 1065 FT /note="L -> V (in dbSNP:rs56395521)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041432" FT VARIANT 1075 FT /note="A -> D (in IRAN type A)" FT /evidence="ECO:0000269|PubMed:8243830" FT /id="VAR_004094" FT VARIANT 1095 FT /note="K -> E (in a subject with non-insulin dependent FT diabetes mellitus; dbSNP:rs909008899)" FT /evidence="ECO:0000269|PubMed:2040394" FT /id="VAR_015924" FT VARIANT 1119 FT /note="R -> W (in LEPRCH; dbSNP:rs1229730671)" FT /evidence="ECO:0000269|PubMed:12970295, FT ECO:0000269|PubMed:9249867" FT /id="VAR_015925" FT VARIANT 1143 FT /note="I -> T (in RMS; reduces insulin binding)" FT /evidence="ECO:0000269|PubMed:10443650, FT ECO:0000269|PubMed:12023989" FT /id="VAR_015926" FT VARIANT 1158 FT /note="R -> Q (in T2D)" FT /evidence="ECO:0000269|PubMed:1470163" FT /id="VAR_015927" FT VARIANT 1158 FT /note="R -> W (in RMS; abolishes insulin binding; FT dbSNP:rs111993466)" FT /evidence="ECO:0000269|PubMed:10443650, FT ECO:0000269|PubMed:12023989" FT /id="VAR_015928" FT VARIANT 1161 FT /note="A -> T (in IRAN type A; dbSNP:rs121913139)" FT /evidence="ECO:0000269|PubMed:2168397" FT /id="VAR_004095" FT VARIANT 1162 FT /note="A -> E (in IRAN type A; impairs proteolytic FT processing; dbSNP:rs121913154)" FT /evidence="ECO:0000269|PubMed:8096518" FT /id="VAR_004096" FT VARIANT 1180 FT /note="M -> I (in a patient with insulin resistance; FT dbSNP:rs121913157)" FT /evidence="ECO:0000269|PubMed:1890161" FT /id="VAR_004097" FT VARIANT 1191 FT /note="R -> Q (in T2D; dbSNP:rs121913150)" FT /evidence="ECO:0000269|PubMed:1607076" FT /id="VAR_004098" FT VARIANT 1201 FT /note="R -> Q (in HHF5 and IRAN type A; interferes with FT kinase activation by insulin; dbSNP:rs121913156)" FT /evidence="ECO:0000269|PubMed:15161766, FT ECO:0000269|PubMed:8082780, ECO:0000269|PubMed:8288049" FT /id="VAR_015929" FT VARIANT 1201 FT /note="R -> W (in LEPRCH and RMS; reduces insulin binding FT possibly due to reduced receptor levels on the cell FT surface; dbSNP:rs1568426700)" FT /evidence="ECO:0000269|PubMed:12023989, FT ECO:0000269|PubMed:9703342" FT /id="VAR_015930" FT VARIANT 1205 FT /note="P -> L (in IRAN type A; moderate; FT dbSNP:rs1295645322)" FT /evidence="ECO:0000269|PubMed:1563582, FT ECO:0000269|PubMed:8314008" FT /id="VAR_004099" FT VARIANT 1206 FT /note="E -> D (in IRAN type A; accelerates degradation of FT the protein and impairs kinase activity)" FT /evidence="ECO:0000269|PubMed:7983039" FT /id="VAR_015931" FT VARIANT 1206 FT /note="E -> K (in LEPRCH)" FT /evidence="ECO:0000269|PubMed:9249867" FT /id="VAR_015932" FT VARIANT 1220 FT /note="W -> L (in IRAN type A; accelerates degradation of FT the protein and impairs kinase activity; dbSNP:rs52800171)" FT /evidence="ECO:0000269|PubMed:7983039, FT ECO:0000269|PubMed:8390949" FT /id="VAR_004100" FT VARIANT 1227 FT /note="W -> S (in IRAN type A; dbSNP:rs121913140)" FT /evidence="ECO:0000269|PubMed:1963473" FT /id="VAR_004101" FT VARIANT 1282 FT /note="T -> A (in dbSNP:rs55875349)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041433" FT VARIANT 1361 FT /note="Y -> C (in dbSNP:rs13306449)" FT /evidence="ECO:0000269|PubMed:7657032" FT /id="VAR_015933" FT VARIANT 1378 FT /note="R -> Q (in IRAN type A; dbSNP:rs52826008)" FT /evidence="ECO:0000269|PubMed:8314008" FT /id="VAR_015934" FT MUTAGEN 991 FT /note="L->A: Reduces interaction with IRS1 but has no FT effect on interaction with SHC1." FT /evidence="ECO:0000269|PubMed:7559478" FT MUTAGEN 992 FT /note="Y->A: Reduces interaction with IRS1 but has no FT effect on interaction with SHC1." FT /evidence="ECO:0000269|PubMed:7559478" FT MUTAGEN 996..997 FT /note="NP->AA: Abolishes interaction with IRS1. Severely FT disrupts, but does not abolish interaction with SHC1." FT /evidence="ECO:0000269|PubMed:7559478" FT MUTAGEN 996 FT /note="N->A: Abolishes interaction with IRS1 and FT significantly reduces interaction with SHC1. Has no effect FT on interaction with PIK3R1." FT /evidence="ECO:0000269|PubMed:7537849, FT ECO:0000269|PubMed:7559478" FT MUTAGEN 997 FT /note="P->A: Abolishes interaction with IRS1 and FT significantly reduces interaction with SHC1. Has no effect FT on interaction with PIK3R1." FT /evidence="ECO:0000269|PubMed:7537849, FT ECO:0000269|PubMed:7559478" FT MUTAGEN 998 FT /note="E->A: Does not affect interaction with IRS1, SHC1 or FT PIK3R1." FT /evidence="ECO:0000269|PubMed:7537849" FT MUTAGEN 999 FT /note="Y->E: Abolishes interaction with IRS1 and SHC1." FT /evidence="ECO:0000269|PubMed:2842060, FT ECO:0000269|PubMed:7537849, ECO:0000269|PubMed:7559478, FT ECO:0000269|PubMed:9428692" FT MUTAGEN 999 FT /note="Y->F: Has no effect on insulin-stimulated FT autophosphorylation, but inhibits the biological activity FT of the receptor. Abolishes interaction with IRS1 and almost FT completely prevents interaction with SHC1. Has no effect on FT interaction with PIK3R1. Abolishes interaction with FT STAT5B." FT /evidence="ECO:0000269|PubMed:2842060, FT ECO:0000269|PubMed:7537849, ECO:0000269|PubMed:7559478, FT ECO:0000269|PubMed:9428692" FT MUTAGEN 1000 FT /note="L->A,R: Severely reduces interaction with SHC1. Has FT no effect on interaction with IRS1." FT /evidence="ECO:0000269|PubMed:7559478" FT MUTAGEN 1002 FT /note="A->D: Reduces interaction with IRS1 but has no FT effect on interaction with SHC1." FT /evidence="ECO:0000269|PubMed:7559478" FT MUTAGEN 1011 FT /note="Y->A: Increases kinase activity." FT /evidence="ECO:0000269|PubMed:12707268" FT MUTAGEN 1057 FT /note="K->A: Abolishes the kinase activity and abolishes FT interaction with IRS1, SHC1, GRB7 and PIK3R1." FT /evidence="ECO:0000269|PubMed:10803466, FT ECO:0000269|PubMed:3101064, ECO:0000269|PubMed:7537849" FT MUTAGEN 1057 FT /note="K->M,R: Abolishes the kinase activity." FT /evidence="ECO:0000269|PubMed:10803466, FT ECO:0000269|PubMed:3101064, ECO:0000269|PubMed:7537849" FT MUTAGEN 1159 FT /note="D->N: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:11598120" FT MUTAGEN 1163 FT /note="R->Q: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:11598120" FT MUTAGEN 1189 FT /note="Y->F: Reduced interaction with GRB7." FT /evidence="ECO:0000269|PubMed:10803466" FT MUTAGEN 1190 FT /note="Y->F: Strongly reduced interaction with GRB7." FT /evidence="ECO:0000269|PubMed:10803466" FT CONFLICT 601 FT /note="D -> N (in Ref. 19; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 830 FT /note="P -> E (in Ref. 19; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 1278 FT /note="K -> N (in Ref. 2; CAA26096)" FT /evidence="ECO:0000305" FT STRAND 33..42 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 45..50 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 53..65 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 70..72 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 73..75 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 83..86 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 88..93 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 100..102 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 103..105 FT /evidence="ECO:0007829|PDB:7MQO" FT STRAND 115..117 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 118..124 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 141..149 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 160..162 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 167..169 FT /evidence="ECO:0007829|PDB:7KD6" FT STRAND 171..175 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 176..178 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 187..192 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 199..201 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 204..206 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 209..211 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 221..223 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 230..232 FT /evidence="ECO:0007829|PDB:7MQO" FT STRAND 243..247 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 251..260 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 263..267 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 273..275 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 276..278 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 279..281 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 283..295 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 298..300 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 305..307 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 310..314 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 319..321 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 323..325 FT /evidence="ECO:0007829|PDB:7KD6" FT STRAND 327..330 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 332..334 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 338..348 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 351..355 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 356..359 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 361..369 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 373..375 FT /evidence="ECO:0007829|PDB:6HN5" FT HELIX 377..385 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 390..393 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 395..399 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 404..406 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 422..424 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 425..430 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 437..439 FT /evidence="ECO:0007829|PDB:4ZXB" FT TURN 441..443 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 447..450 FT /evidence="ECO:0007829|PDB:6HN5" FT STRAND 452..458 FT /evidence="ECO:0007829|PDB:2HR7" FT HELIX 463..472 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 476..478 FT /evidence="ECO:0007829|PDB:2HR7" FT TURN 481..483 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 486..490 FT /evidence="ECO:0007829|PDB:2HR7" FT STRAND 498..500 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 502..507 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 512..516 FT /evidence="ECO:0007829|PDB:6PXW" FT HELIX 524..526 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 527..534 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 538..540 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 552..554 FT /evidence="ECO:0007829|PDB:6HN5" FT STRAND 557..561 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 570..573 FT /evidence="ECO:0007829|PDB:6HN5" FT STRAND 578..580 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 588..597 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 601..603 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 608..610 FT /evidence="ECO:0007829|PDB:4ZXB" FT STRAND 613..616 FT /evidence="ECO:0007829|PDB:6PXW" FT STRAND 626..631 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 633..636 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 638..643 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 654..658 FT /evidence="ECO:0007829|PDB:6PXV" FT HELIX 666..669 FT /evidence="ECO:0007829|PDB:6PXV" FT HELIX 732..740 FT /evidence="ECO:0007829|PDB:7KD6" FT STRAND 798..803 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 805..809 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 817..827 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 838..843 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 858..861 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 867..870 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 881..890 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 896..901 FT /evidence="ECO:0007829|PDB:6PXV" FT HELIX 902..908 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 910..913 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 918..931 FT /evidence="ECO:0007829|PDB:6PXV" FT STRAND 940..944 FT /evidence="ECO:0007829|PDB:6PXV" FT HELIX 953..979 FT /evidence="ECO:0007829|PDB:2MFR" FT STRAND 992..995 FT /evidence="ECO:0007829|PDB:5U1M" FT TURN 1003..1005 FT /evidence="ECO:0007829|PDB:4XLV" FT HELIX 1009..1011 FT /evidence="ECO:0007829|PDB:1IR3" FT HELIX 1014..1016 FT /evidence="ECO:0007829|PDB:1IRK" FT HELIX 1020..1022 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1023..1031 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1033..1043 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1046..1048 FT /evidence="ECO:0007829|PDB:2Z8C" FT STRAND 1050..1057 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1065..1078 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1089..1093 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1095..1098 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1100..1104 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1111..1117 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1119..1121 FT /evidence="ECO:0007829|PDB:3ETA" FT HELIX 1133..1152 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1154..1156 FT /evidence="ECO:0007829|PDB:2AUH" FT HELIX 1162..1164 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1165..1167 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1173..1175 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1181..1183 FT /evidence="ECO:0007829|PDB:1IRK" FT TURN 1185..1187 FT /evidence="ECO:0007829|PDB:3BU3" FT STRAND 1190..1192 FT /evidence="ECO:0007829|PDB:5HHW" FT STRAND 1194..1198 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1200..1202 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1205..1210 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1215..1230 FT /evidence="ECO:0007829|PDB:3BU3" FT TURN 1236..1239 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1242..1250 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1263..1272 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1277..1279 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1283..1290 FT /evidence="ECO:0007829|PDB:3BU3" FT HELIX 1291..1293 FT /evidence="ECO:0007829|PDB:5HHW" FT HELIX 1298..1301 FT /evidence="ECO:0007829|PDB:3BU3" FT TURN 1303..1305 FT /evidence="ECO:0007829|PDB:4XLV" FT HELIX 1307..1309 FT /evidence="ECO:0007829|PDB:8DWN" SQ SEQUENCE 1382 AA; 156333 MW; 709A955660739066 CRC64; MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK DLFPNLTVIR GSRLFFNYAL VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN ELCYLATIDW SRILDSVEDN YIVLNKDDNE ECGDICPGTA KGKTNCPATV INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHSECL GNCSQPDDPT KCVACRNFYL DGRCVETCPP PYYHFQDWRC VNFSFCQDLH HKCKNSRRQG CHQYVIHNNK CIPECPSGYT MNSSNLLCTP CLGPCPKVCH LLEGEKTIDS VTSAQELRGC TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGYLKIRRS YALVSLSFFR KLRLIRGETL EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ GKLFFHYNPK LCLSEIHKME EVSGTKGRQE RNDIALKTNG DQASCENELL KFSYIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ NVTEFDGQDA CGSNSWTVVD IDPPLRSNDP KSQNHPGWLM RGLKPWTQYA IFVKTLVTFS DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SEDSQKHNQS EYEDSAGECC SCPKTDSQIL KELEESSFRK TFEDYLHNVV FVPRKTSSGT GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV SRKHFALERG CRLRGLSPGN YSVRIRATSL AGNGSWTEPT YFYVTDYLDV PSNIAKIIIG PLIFVFLFSV VIGSIYLFLR KRQPDGPLGP LYASSNPEYL SASDVFPCSV YVPDEWEVSR EKITLLRELG QGSFGMVYEG NARDIIKGEA ETRVAVKTVN ESASLRERIE FLNEASVMKG FTCHHVVRLL GVVSKGQPTL VVMELMAHGD LKSYLRSLRP EAENNPGRPP PTLQEMIQMA AEIADGMAYL NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV RWMAPESLKD GVFTTSSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM DGGYLDQPDN CPERVTDLMR MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE VSFFHSEENK APESEELEME FEDMENVPLD RSSHCQREEA GGRDGGSSLG FKRSYEEHIP YTHMNGGKKN GRILTLPRSN PS //