ID INSR_HUMAN Reviewed; 1382 AA. AC P06213; Q17RW0; Q59H98; Q9UCB7; Q9UCB8; Q9UCB9; DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot. DT 28-JUL-2009, sequence version 3. DT 03-NOV-2009, entry version 150. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANTS HIS-171; RP THR-448 AND LYS-492. RX MEDLINE=85176928; PubMed=2859121; DOI=10.1016/0092-8674(85)90334-4; RA Ebina Y., Ellis L., Jarnagin K., Edery M., Graf L., Clauser E., RA Ou J.-H., 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 RP AND 763-782, AND GLYCOSYLATION AT ASN-43 AND ASN-769. RX MEDLINE=85137889; PubMed=2983222; DOI=10.1038/313756a0; RA Ullrich A., Bell J.R., Chen E.Y., Herrera R., Petruzzelli L.M., RA Dull T.J., Gray A., Coussens L., Liao Y.-C., Tsubokawa M., Mason A., RA Seeburg P.H., Grunfeld C., Rosen O.M., Ramachandran J.; RT "Human insulin receptor and its relationship to the tyrosine kinase RT family 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]. RC TISSUE=Fetal liver; RX MEDLINE=91006864; PubMed=2210055; RA Seino S., Seino M., Bell G.I.; RT "Human insulin-receptor gene. Partial sequence and amplification of RT exons by polymerase chain reaction."; RL Diabetes 39:123-128(1990). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ALA-2. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M., RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., RA 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). 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33. RX MEDLINE=88058985; PubMed=3680248; 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. RX MEDLINE=90032206; 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. RX MEDLINE=89380228; PubMed=2777789; RA Tewari D.S., Cook D.M., Taub R.; RT "Characterization of the promoter region and 3' end of the human RT insulin receptor gene."; RL J. Biol. Chem. 264:16238-16245(1989). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33. RC TISSUE=Skin fibroblast; RX MEDLINE=91125373; PubMed=2280779; 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 RT 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. RC TISSUE=Placenta; RX MEDLINE=91009374; PubMed=2211730; RA Xu Q.-Y., Paxton R.J., Fujita-Yamaguchi Y.; RT "Substructural analysis of the insulin receptor by microsequence RT analyses of limited tryptic fragments isolated by sodium dodecyl RT sulfate-polyacrylamide gel electrophoresis in the absence or presence RT of 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 RP HYBRID RECEPTOR WITH IGF1R. RC TISSUE=Placenta; RX MEDLINE=94079885; 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- RT I/insulin hybrid receptors by protein microsequencing and RT 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 MEDLINE=89165872; 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 RP SPECIFICITY, LIGAND-BINDING, AND AUTOPHOSPHORYLATION. RX MEDLINE=90316094; PubMed=2369896; RA Mosthaf L., Grako K., Dull T.J., Coussens L., Ullrich A., RA 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 MEDLINE=89252471; PubMed=2566545; RA Elbein S.C.; RT "Molecular and clinical characterization of an insertional RT polymorphism of 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 AUTOPHOSPHORYLATION. RC TISSUE=Placenta; RX MEDLINE=88326279; PubMed=3166375; 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 RT peptide mapping."; RL Biochem. J. 252:607-615(1988). RN [18] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1006-1123. RX MEDLINE=89298408; 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 RT domain of the insulin receptor."; RL Science 245:63-66(1989). RN [19] RP PARTIAL PROTEIN SEQUENCE. RX MEDLINE=88190050; 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 MEDLINE=87118237; PubMed=3101064; DOI=10.1073/pnas.84.3.704; RA Ebina Y., Araki E., Taira M., Shimada F., Mori M., Craik C.S., RA Siddle K., Pierce S.B., Roth R.A., Rutter W.J.; RT "Replacement of lysine residue 1030 in the putative ATP-binding region RT of the insulin receptor abolishes insulin- and antibody-stimulated RT glucose 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 MEDLINE=88311065; 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., RA Ullrich A., 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 MEDLINE=92337603; 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 RT receptor 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 MEDLINE=93112026; 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 RT the 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; 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; RA Van Horn D.J., Myers M.G. Jr., Backer J.M.; RT "Direct activation of the phosphatidylinositol 3'-kinase by the RT insulin 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 MEDLINE=96007458; 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 RT with 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; 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 RT non-SH2 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; 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 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 RT in human tissues."; RL Mol. Cell. Endocrinol. 129:121-126(1997). RN [30] RP INTERACTION WITH SORBS1. RX MEDLINE=21269187; 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 RT domain containing 1 (SORBS1) gene: a protein associated with c-Abl RT during insulin signaling in the hepatoma cell line Hep3B."; RL Genomics 74:12-20(2001). RN [31] 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 [32] 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 RT islets of Langerhans."; RL J. Clin. Invest. 115:2462-2471(2005). RN [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1189, AND MASS RP SPECTROMETRY. RC TISSUE=Epithelium; RX PubMed=15951569; DOI=10.1074/mcp.M500089-MCP200; RA Zhang Y., Wolf-Yadlin A., Ross P.L., Pappin D.J., Rush J., RA Lauffenburger D.A., White F.M.; RT "Time-resolved mass spectrometry of tyrosine phosphorylation sites in RT the epidermal growth factor receptor signaling network reveals dynamic RT modules."; RL Mol. Cell. Proteomics 4:1240-1250(2005). RN [34] 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 RT growth factor I receptor (IGF-IR) have low insulin and high IGF-1 RT affinity irrespective of the IR splice variant."; RL J. Biol. Chem. 281:25869-25874(2006). RN [35] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1185; TYR-1189 AND RP TYR-1190, AND MASS SPECTROMETRY. RX PubMed=18083107; DOI=10.1016/j.cell.2007.11.025; RA Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., RA Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., RA Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J., RA Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., RA Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.; RT "Global survey of phosphotyrosine signaling identifies oncogenic RT kinases in lung cancer."; RL Cell 131:1190-1203(2007). RN [36] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1354, AND MASS RP SPECTROMETRY. RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of RT the kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [37] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-400; TYR-401 AND RP SER-407, AND MASS SPECTROMETRY. 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 [38] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-242 AND ASN-541, AND MASS RP SPECTROMETRY. 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 RT multiple enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [39] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-445 AND ASN-920, AND MASS RP SPECTROMETRY. 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- RT linked cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [40] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1112, AND MASS SPECTROMETRY. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [41] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310. RX MEDLINE=95089813; 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 [42] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1005-1310. RX MEDLINE=97459943; PubMed=9312016; DOI=10.1093/emboj/16.18.5572; RA Hubbard S.R.; RT "Crystal structure of the activated insulin receptor tyrosine kinase RT in complex with peptide substrate and ATP analog."; RL EMBO J. 16:5572-5581(1997). RN [43] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH RP SH2B2. 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 [44] RP VARIANT IRAN TYPE A SER-762. RX MEDLINE=88204915; 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 RT insulin proreceptor processing."; RL Science 240:784-787(1988). RN [45] RP VARIANT LEPRECHAUNISM GLU-487. RX MEDLINE=88204916; PubMed=2834824; DOI=10.1126/science.2834824; RA Kadowaki T., Bevins C., Cama A., Ojamaa K., Marcus-Samuels B., RA Kadowaki H., Beitz L., McKeon C., Taylor S.I.; RT "Two mutant alleles of the insulin receptor gene in a patient with RT extreme insulin resistance."; RL Science 240:787-790(1988). RN [46] RP VARIANT LEPRECHAUNISM PRO-260. RX MEDLINE=90060008; PubMed=2479553; 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 RT with insulin resistance."; RL EMBO J. 8:2503-2507(1989). RN [47] RP VARIANT IRAN TYPE A VAL-1035. RX MEDLINE=89298409; PubMed=2544998; DOI=10.1126/science.2544998; RA Odawara M., Kadowaki T., Yamamoto R., Shibasaki Y., Tobe K., RA Accili D., Bevins C., Mikami Y., Matsuura N., Akanuma Y., Takaku F., RA Taylor S.I., Kasuga M.; RT "Human diabetes associated with a mutation in the tyrosine kinase RT domain of the insulin receptor."; RL Science 245:66-68(1989). RN [48] RP VARIANT IRAN TYPE A THR-1161. RX MEDLINE=90368673; PubMed=2168397; 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 RT impairs tyrosine kinase function and is associated with dominantly RT inherited insulin resistance."; RL J. Biol. Chem. 265:14979-14985(1990). RN [49] RP CHARACTERIZATION OF VARIANT RMS LYS-42. RX MEDLINE=91035445; PubMed=2121734; RA Kadowaki T., Kadowaki H., Accili D., Taylor S.I.; RT "Substitution of lysine for asparagine at position 15 in the alpha- RT subunit of the human insulin receptor. A mutation that impairs RT transport of receptors to the cell surface and decreases the affinity RT of insulin binding."; RL J. Biol. Chem. 265:19143-19150(1990). RN [50] RP VARIANT RMS LYS-42, VARIANT LEPRECHAUNISM ARG-236, AND VARIANT IRAN RP TYPE A SER-489. RX MEDLINE=90307970; 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 RT genetic forms of insulin resistance."; RL J. Clin. Invest. 86:254-264(1990). RN [51] RP VARIANT IRAN TYPE A SER-1227. RX MEDLINE=91155951; PubMed=1963473; RA Moller D.E., Yokota A., Ginsberg-Fellner F., Flier J.S.; RT "Functional properties of a naturally occurring Trp1200-->Ser1200 RT mutation of the insulin receptor."; RL Mol. Endocrinol. 4:1183-1191(1990). RN [52] RP VARIANT GLU-1095. RX MEDLINE=91250037; PubMed=2040394; RA O'Rahilly S., Choi W.H., Patel P., Turner R.C., Flier J.S., RA 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 [53] RP VARIANT IRAN TYPE A GLN-1020. RX MEDLINE=91161622; PubMed=2002058; 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 RT tyrosine kinase domain of both insulin receptor gene alleles."; RL J. Biol. Chem. 266:5260-5267(1991). RN [54] RP VARIANT INS RESISTANCE ILE-1180. RX MEDLINE=91365848; PubMed=1890161; 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 [55] RP VARIANTS LEPRECHAUNISM ALA-55 AND ARG-393. RX MEDLINE=92299170; PubMed=1607067; 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 RT gradient gel electrophoresis."; RL Diabetes 41:408-415(1992). RN [56] RP VARIANT NIDDM GLN-1191. RX MEDLINE=92299185; PubMed=1607076; 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 [57] RP VARIANT INS RESISTANCE LEU-1205. RX MEDLINE=92225265; 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 [58] RP VARIANT LEPRECHAUNISM ARG-58. RX MEDLINE=92112725; PubMed=1730625; 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, RT linked to insulin resistance, inhibits receptor processing and RT transport."; RL J. Biol. Chem. 267:66-71(1992). RN [59] RP VARIANT INS RESISTANCE GLN-1158. RX MEDLINE=93109267; PubMed=1470163; RA Kasuga M., Kishimoto M., Hashiramoto M., Yonezawa K., Kazumi T., RA Hagino H., Shii K.; RT "Insulin receptor Arg1131-->Gln: a novel mutation in the catalytic RT loop of insulin receptor observed in insulin resistant diabetes."; RL Nihon Geka Gakkai Zasshi 93:968-971(1992). RN [60] RP VARIANT MET-1012. RX MEDLINE=93162359; PubMed=8432414; RA Elbein S.C., Sorensen L.K., Schumacher M.C.; RT "Methionine for valine substitution in exon 17 of the insulin receptor RT gene in a pedigree with familial NIDDM."; RL Diabetes 42:429-434(1993). RN [61] RP VARIANT INS RESISTANCE ASP-1075. RX MEDLINE=94063262; PubMed=8243830; 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 RT causes defective kinase activity and insulin resistance."; RL Diabetes 42:1837-1844(1993). RN [62] RP VARIANT MET-1012. RX MEDLINE=93209491; 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- RT Berardinelli type, express normal insulin receptors."; RL Diabetologia 36:172-174(1993). RN [63] RP VARIANT INS RESISTANCE LEU-1220. RX MEDLINE=93300291; 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 RT resistance."; RL Diabetologia 36:414-422(1993). RN [64] RP VARIANT INS RESISTANCE LEU-220. RX MEDLINE=94061041; 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., RA Micossi P., Barbetti F.; RT "Substitution of Leu for Pro-193 in the insulin receptor in a patient RT with a genetic form of severe insulin resistance."; RL Hum. Mol. Genet. 2:1437-1441(1993). RN [65] RP CHARACTERIZATION OF VARIANT IRAN TYPE A GLU-1162. RX MEDLINE=93216782; PubMed=8096518; RA Cama A., de la Luz Sierra M., Quon M.J., Ottini L., Gorden P., RA Taylor S.I.; RT "Substitution of glutamic acid for alanine 1135 in the putative RT 'catalytic loop' of the tyrosine kinase domain of the human insulin RT receptor. A mutation that impairs proteolytic processing into subunits RT and inhibits receptor tyrosine kinase activity."; RL J. Biol. Chem. 268:8060-8069(1993). RN [66] RP VARIANT INS RESISTANCE VAL-409. RX MEDLINE=93266582; PubMed=8388389; 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 RT valine 382."; RL J. Biol. Chem. 268:11272-11277(1993). RN [67] RP VARIANT LEPRECHAUNISM MET-146. RX MEDLINE=93316277; PubMed=8326490; RA Al-Gazali L.I., Khalil M., Devadas K.; RT "A syndrome of insulin resistance resembling leprechaunism in five RT sibs of consanguineous parents."; RL J. Med. Genet. 30:470-475(1993). RN [68] RP VARIANT LEPRECHAUNISM PRO-113. RX MEDLINE=93126382; 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 RT insulin receptor."; RL Proc. Natl. Acad. Sci. U.S.A. 90:60-64(1993). RN [69] RP VARIANT IRAN TYPE A GLN-1201. RX MEDLINE=94116755; PubMed=8288049; RA Moller D.E., Cohen O., Yamaguchi Y., Assiz R., Grigorescu F., RA Eberle A., 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 [70] RP VARIANT RMS SYNDROME LEU-350, VARIANTS INS RESISTANCE LEU-1205 AND RP GLN-1378, AND VARIANT MET-1012. RX MEDLINE=94148142; PubMed=8314008; 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 RT insulin resistance."; RL Diabetes 43:357-368(1994). RN [71] RP CHARACTERIZATION OF VARIANT IRAN TYPE A GLN-1201. RX MEDLINE=94364485; 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 RT the tyrosine kinase domain of the insulin receptor from a type A RT insulin resistant patient."; RL FEBS Lett. 351:276-280(1994). RN [72] RP VARIANT LEPRECHAUNISM SER-439. RX MEDLINE=94245758; PubMed=8188715; RA van der Vorm E.R., Kuipers A., Kielkopf-Renner S., Krans H.M.J., RA Moller W., Maassen J.A.; RT "A mutation in the insulin receptor that impairs proreceptor RT processing but not insulin binding."; RL J. Biol. Chem. 269:14297-14302(1994). RN [73] RP CHARACTERIZATION OF VARIANTS INS RESISTANCE ASP-1206 AND LEU-1220. RX MEDLINE=95074138; PubMed=7983039; 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 RT receptor accelerate degradation of the insulin receptor and impair the RT kinase activity."; RL J. Biol. Chem. 269:31019-31027(1994). RN [74] RP VARIANT LEPRECHAUNISM MET-146. RX MEDLINE=95115010; PubMed=7815442; RA Hone J., Accili D., al-Gazali L.I., Lestringant G., Orban T., RA Taylor S.I.; RT "Homozygosity for a new mutation (Ile119-->Met) in the insulin RT receptor gene in five sibs with familial insulin resistance."; RL J. Med. Genet. 31:715-716(1994). RN [75] RP VARIANT NIDDM ALA-858, AND VARIANT CYS-1361. RX MEDLINE=95385853; PubMed=7657032; RA Kan M., Kanai F., Iida M., Jinnouchi H., Todaka M., Imanaka T., RA Ito K., Nishioka Y., Ohnishi T., Kamohara S., Hayashi H., Murakami T., RA Kagawa S., Sano H., Hashimoto N., Yoshida S., Makino H., Ebina Y.; RT "Frequency of mutations of insulin receptor gene in Japanese patients RT with NIDDM."; RL Diabetes 44:1081-1086(1995). RN [76] RP VARIANT LEPRECHAUNISM ASN-308 DEL. RX MEDLINE=95263703; PubMed=7538143; DOI=10.1210/jc.80.5.1496; 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 [77] RP VARIANT PHE-1023. RX MEDLINE=97045807; PubMed=8890729; 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 RT extreme insulin resistance in association with defective insulin RT binding: a case report."; RL Eur. J. Endocrinol. 135:357-363(1996). RN [78] RP VARIANT LEPRECHAUNISM ASN-308 DEL. RX MEDLINE=96225546; PubMed=8636294; DOI=10.1210/jc.81.2.719; 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 [79] RP VARIANT MET-1012. RX MEDLINE=97342928; PubMed=9199575; 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 RT population: lack of associations with non-insulin-dependent diabetes RT mellitus or insulin resistance."; RL Am. J. Hum. Genet. 60:1532-1535(1997). RN [80] RP VARIANTS INS RESISTANCE GLY-86 AND PRO-89. RX MEDLINE=97318853; 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 [81] RP CHARACTERIZATION OF VARIANT LEPRECHAUNISM MET-937. RX MEDLINE=97445067; PubMed=9299395; DOI=10.1006/bbrc.1997.7181; RA Kadowaki H., Takahashi Y., Ando A., Momomura K., Kaburagi Y., RA Quin J.D., MacCuish A.C., Koda N., Fukushima Y., Taylor S.I., RA Akanuma Y., Yazaki Y., Kadowaki T.; RT "Four mutant alleles of the insulin receptor gene associated with RT genetic syndromes of extreme insulin resistance."; RL Biochem. Biophys. Res. Commun. 237:516-520(1997). RN [82] RP VARIANTS LEPRECHAUNISM TRP-1119 AND LYS-1206. RX MEDLINE=97393350; 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., RA Amselem S.; RT "Molecular analysis of the insulin receptor gene for prenatal RT diagnosis of leprechaunism in two families."; RL Prenat. Diagn. 17:657-663(1997). RN [83] RP VARIANTS LEPRECHAUNISM TYR-301 AND TRP-1201. RX MEDLINE=98366902; PubMed=9703342; RA Whitehead J.P., Soos M.A., Jackson R., Tasic V., Kocova M., RA O'Rahilly S.; RT "Multiple molecular mechanisms of insulin receptor dysfunction in a RT patient with Donohue syndrome."; RL Diabetes 47:1362-1364(1998). RN [84] RP VARIANTS RMS THR-1143 AND TRP-1158. RX MEDLINE=99371250; PubMed=10443650; DOI=10.1210/jc.84.8.2623; RA Longo N., Wang Y., Pasquali M.; RT "Progressive decline in insulin levels in Rabson-Mendenhall RT syndrome."; RL J. Clin. Endocrinol. Metab. 84:2623-2629(1999). RN [85] RP VARIANTS INS RESISTANCE LEU-167 AND VAL-1055. RX MEDLINE=20195376; PubMed=10733238; RX DOI=10.1034/j.1399-0004.2000.570110.x; RA Rique S., Nogues C., Ibanez L., Marcos M.V., Ferragut J., RA Carrascosa A., Potau N.; RT "Identification of three novel mutations in the insulin receptor gene RT in type A insulin resistant patients."; RL Clin. Genet. 57:67-69(2000). RN [86] RP VARIANT INS RESISTANCE TYR-280. RX MEDLINE=21159654; PubMed=11260230; RX DOI=10.1034/j.1399-0004.2001.590309.x; RA Osawa H., Nishimiya T., Ochi M., Niiya T., Onuma H., Kitamuro F., RA Kaino Y., Kida K., Makino H.; RT "Identification of novel C253Y missense and Y864X nonsense mutations RT in the insulin receptor gene in type A insulin-resistant patients."; RL Clin. Genet. 59:194-197(2001). RN [87] RP VARIANT INS RESISTANCE CYS-279. RX MEDLINE=22102292; PubMed=12107746; DOI=10.1007/s00125-002-0798-5; RA Hamer I., Foti M., Emkey R., Cordier-Bussat M., Philippe J., RA De Meyts P., Maeder C., Kahn C.R., Carpentier J.-L.; RT "An arginine to cysteine(252) mutation in insulin receptors from a RT patient with severe insulin resistance inhibits receptor RT internalisation but preserves signalling events."; RL Diabetologia 45:657-667(2002). RN [88] RP CHARACTERIZATION OF VARIANTS LEPRECHAUNISM PRO-113; VAL-119; ASN-308 RP DEL; THR-925 AND TRP-926, AND VARIANTS RMS THR-997; THR-1143; TRP-1158 RP AND TRP-1201. RX MEDLINE=22021354; 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 RT resistance."; RL Hum. Mol. Genet. 11:1465-1475(2002). RN [89] RP VARIANT LEPRECHAUNISM VAL-362 DEL. RX MEDLINE=22426011; PubMed=12538626; DOI=10.1210/en.2002-220815; RA George S., Johansen A., Soos M.A., Mortensen H., Gammeltoft S., RA Saudek V., Siddle K., Hansen L., O'Rahilly S.; RT "Deletion of V335 from the L2 domain of the insulin receptor results RT in a conformationally abnormal receptor that is unable to bind insulin RT and causes Donohue's syndrome in a human subject."; RL Endocrinology 144:631-637(2003). RN [90] RP VARIANT IRAN TYPE A HIS-279, VARIANTS LEPRECHAUNISM GLN-120; LEU-350; RP ASP-458 AND TRP-1119, CHARACTERIZATION OF VARIANT IRAN TYPE A HIS-279, RP AND CHARACTERIZATION OF VARIANTS LEPRECHAUNISM 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 [91] RP VARIANT HHF5 GLN-1201. RX PubMed=15161766; RA Hoejlund K., Hansen T., Lajer M., Henriksen J.E., Levin K., RA Lindholm J., 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 [92] 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 [93] 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., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: This receptor binds insulin and has a tyrosine-protein CC kinase activity. Isoform Short has a higher affinity for insulin. CC Mediates the metabolic functions of insulin. Binding to insulin CC stimulates association of the receptor with downstream mediators CC including IRS1 and phosphatidylinositol 3'-kinase (PI3K). Can CC activate PI3K either directly by binding to the p85 regulatory CC subunit, or indirectly via IRS1. When present in a hybrid receptor CC with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid CC receptors composed of IGF1R and INSR isoform Long are activated CC with a high affinity by IGF1, with low affinity by IGF2 and not CC significantly activated by insulin, and that hybrid receptors CC composed of IGF1R and INSR isoform Short are activated by IGF1, CC IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid CC receptors composed of IGF1R and INSR isoform Long and hybrid CC receptors composed of IGF1R and INSR isoform Short have similar CC binding characteristics, both bind IGF1 and have a low affinity CC for insulin. CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a CC [protein]-L-tyrosine phosphate. CC -!- ENZYME REGULATION: Autophosphorylation activates the kinase CC activity. CC -!- SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide CC bonds. The alpha chains contribute to the formation of the ligand- CC binding domain, while the beta chains carry the kinase domain. CC Interacts with SORBS1 but dissociates from it following insulin CC stimulation. Binds SH2B2. Interacts with the PTB/PID domains of CC IRS1 and SHC1 in vitro when autophosphorylated on tyrosine CC residues. The sequences surrounding the phosphorylated NPXY motif CC contribute differentially to either IRS1 or SHC1 recognition. CC Interacts with the SH2 domains of the 85 kDa regulatory subunit of CC PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine CC residues. Interacts with SOCS7. Forms a hybrid receptor with CC IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 CC beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. CC Interacts with CAV2 (tyrosine-phosphorylated form); the CC interaction is increased with 'Tyr-27'phosphorylation of CAV2 (By CC similarity). CC -!- INTERACTION: CC P18031:PTPN1; NbExp=1; IntAct=EBI-475899, EBI-968788; CC Q05209:PTPN12; NbExp=1; IntAct=EBI-475899, EBI-2266035; CC P23467:PTPRB; NbExp=1; IntAct=EBI-475899, EBI-1265766; CC P08575:PTPRC; NbExp=1; IntAct=EBI-475899, EBI-1341; CC P23470:PTPRG; NbExp=1; IntAct=EBI-475899, EBI-2258115; CC Q12913:PTPRJ; NbExp=1; IntAct=EBI-475899, EBI-2264500; CC Q15262:PTPRK; NbExp=1; IntAct=EBI-475899, EBI-474052; CC Q16827:PTPRO; NbExp=1; IntAct=EBI-475899, EBI-723739; CC Q9BX66:SORBS1; NbExp=1; IntAct=EBI-475899, EBI-433642; CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane CC protein. 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: Found as a hybrid receptor with IGF1R in CC muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, CC fibrobasts, spleen and placenta (at protein level). Isoform Long CC and isoform Short are expressed in the peripheral nerve, kidney, CC liver, striated muscle, fibroblasts and skin. Isoform Short is CC expressed also in the spleen and lymphoblasts. 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 CC plasma membrane. CC -!- PTM: Autophosphorylated on tyrosine residues in response to CC insulin. CC -!- PTM: Phosphorylation of Tyr-999 is required for IRS1- and SHC1- CC binding. CC -!- DISEASE: Defects in INSR are the cause of insulin resistance (Ins CC resistance) [MIM:125853]. CC -!- DISEASE: Defects in INSR are the cause of Rabson-Mendenhall CC syndrome (RMS) [MIM:262190]; also known as Mendenhall syndrome. CC RMS is a severe insulin resistance syndrome characterized by CC insulin-resistant diabetes mellitus with pineal hyperplasia and CC somatic abnormalities. Typical features include coarse, senile- CC appearing facies, dental and skin abnormalities, abdominal CC distension, and phallic enlargement. Inheritance is autosomal CC recessive. CC -!- DISEASE: Defects in INSR are the cause of leprechaunism CC [MIM:246200]; also known as Donohue syndrome. Leprechaunism CC represents the most severe form of insulin resistance syndrome, CC characterized by intrauterine and postnatal growth retardation and CC death in early infancy. Inheritance is autosomal recessive. CC -!- DISEASE: Defects in INSR may be associated with noninsulin- CC dependent diabetes mellitus (NIDDM) [MIM:125853]; also known as CC diabetes mellitus type 2. CC -!- DISEASE: Defects in INSR are the cause of familial CC hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:609968]. Familial CC hyperinsulinemic hypoglycemia [MIM:256450], also referred to as CC congenital hyperinsulinism, nesidioblastosis, or persistent CC hyperinsulinemic hypoglycemia of infancy (PPHI), is the most CC common cause of persistent hypoglycemia in infancy and is due to CC defective negative feedback regulation of insulin secretion by low CC glucose levels. CC -!- DISEASE: Defects in INSR are the cause of insulin-resistant CC diabetes mellitus with acanthosis nigricans type A (IRAN type A) CC [MIM:610549]. This syndrome is characterized by the association of CC severe insulin resistance (manifested by marked hyperinsulinemia CC and a failure to respond to exogenous insulin) with the skin CC lesion acanthosis nigricans and ovarian hyperandrogenism in CC adolescent female subjects. Women frequently present with CC hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. CC This syndrome is different from the type B that has been CC demonstrated to be secondary to the presence of circulating CC autoantibodies against the insulin receptor. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. Insulin receptor subfamily. CC -!- SIMILARITY: Contains 3 fibronectin type-III domains. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Insulin receptor entry; CC URL="http://en.wikipedia.org/wiki/Insulin_receptor"; CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/INSR"; 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 IPI; IPI00025803; -. DR IPI; IPI00220325; -. DR PIR; A37348; INHUR. DR RefSeq; NP_000199.2; -. DR RefSeq; NP_001073285.1; -. DR UniGene; Hs.465744; -. 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=1005-1298. 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; 2DTG; X-ray; 3.80 A; E=28-943. DR PDB; 2HR7; X-ray; 2.32 A; A/B=28-512. DR PDB; 2Z8C; X-ray; 3.25 A; A=1009-1310. 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 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; 2DTG; -. DR PDBsum; 2HR7; -. DR PDBsum; 2Z8C; -. DR PDBsum; 3BU3; -. DR PDBsum; 3BU5; -. DR PDBsum; 3BU6; -. DR PDBsum; 3EKK; -. DR PDBsum; 3EKN; -. DR PDBsum; 3ETA; -. DR DIP; DIP:480N; -. DR DIP; DIP:6025N; -. DR IntAct; P06213; 20. DR STRING; P06213; -. DR PhosphoSite; P06213; -. DR Ensembl; ENST00000302850; ENSP00000303830; ENSG00000171105; Homo sapiens. DR Ensembl; ENST00000341500; ENSP00000342838; ENSG00000171105; Homo sapiens. DR GeneID; 3643; -. DR KEGG; hsa:3643; -. DR UCSC; uc002mgd.1; human. DR UCSC; uc002mge.1; human. DR CTD; 3643; -. DR GeneCards; GC19M007067; -. DR HGNC; HGNC:6091; INSR. DR HPA; CAB013113; -. 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 Orphanet; 2297; Insulin-resistance syndrome, type A. DR Orphanet; 508; Leprechaunism. DR Orphanet; 657; Persistent hyperinsulinemic hypoglycemia of infancy. DR Orphanet; 769; Rabson-Mendenhall syndrome. DR PharmGKB; PA202; -. DR HOGENOM; P06213; -. DR HOVERGEN; P06213; -. DR BRENDA; 2.7.10.1; 247. DR Pathway_Interaction_DB; insulin_pathway; Insulin Pathway. DR Pathway_Interaction_DB; insulin_glucose_pathway; Insulin-mediated glucose transport. DR Pathway_Interaction_DB; mtor_4pathway; mTOR signaling pathway. DR Pathway_Interaction_DB; ptp1bpathway; Signaling events mediated by PTP1B. DR Reactome; REACT_498; Signaling by Insulin receptor. DR Reactome; REACT_508; Signal attenuation. DR DrugBank; DB00047; Insulin Glargine recombinant. DR DrugBank; DB00030; Insulin recombinant. DR DrugBank; DB00071; Insulin, porcine. DR ArrayExpress; P06213; -. DR Bgee; P06213; -. DR CleanEx; HS_INSR; -. DR Genevestigator; P06213; -. DR GermOnline; ENSG00000171105; Homo sapiens. DR GO; GO:0005901; C:caveola; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; EXP:Reactome. DR GO; GO:0005899; C:insulin receptor complex; IMP:UniProtKB. DR GO; GO:0005792; C:microsome; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB. 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:UniProtKB. DR GO; GO:0031995; F:insulin-like growth factor II binding; IPI:UniProtKB. DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IDA:UniProtKB. DR GO; GO:0043548; F:phosphoinositide 3-kinase binding; IPI:UniProtKB. DR GO; GO:0051425; F:PTB domain binding; IPI:UniProtKB. DR GO; GO:0004716; F:receptor signaling protein tyrosine kinase ...; IDA:UniProtKB. DR GO; GO:0042169; F:SH2 domain binding; IPI:UniProtKB. DR GO; GO:0000187; P:activation of MAPK activity; IMP:UniProtKB. DR GO; GO:0032148; P:activation of protein kinase B activity; IDA:UniProtKB. DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:UniProtKB-KW. DR GO; GO:0007186; P:G-protein coupled receptor protein signalin...; IDA:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB. DR GO; GO:0003007; P:heart morphogenesis; IMP:UniProtKB. DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:UniProtKB. DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:UniProtKB. DR GO; GO:0048639; P:positive regulation of developmental growth; IMP:UniProtKB. DR GO; GO:0045740; P:positive regulation of DNA replication; IMP:UniProtKB. DR GO; GO:0046326; P:positive regulation of glucose import; IDA:UniProtKB. DR GO; GO:0045725; P:positive regulation of glycogen biosyntheti...; IDA:UniProtKB. DR GO; GO:0045821; P:positive regulation of glycolysis; IMP:UniProtKB. DR GO; GO:0043410; P:positive regulation of MAPKKK cascade; IMP:UniProtKB. DR GO; GO:0045840; P:positive regulation of mitosis; IMP:UniProtKB. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynt...; IMP:UniProtKB. DR GO; GO:0001934; P:positive regulation of protein amino acid p...; IDA:UniProtKB. DR GO; GO:0051897; P:positive regulation of protein kinase B sig...; IMP:UniProtKB. DR GO; GO:0060267; P:positive regulation of respiratory burst; IDA:UniProtKB. DR GO; GO:0046777; P:protein amino acid autophosphorylation; IMP:UniProtKB. DR GO; GO:0051290; P:protein heterotetramerization; IDA:UniProtKB. DR GO; GO:0045995; P:regulation of embryonic development; IMP:UniProtKB. DR GO; GO:0032583; P:regulation of gene-specific transcription; IMP:UniProtKB. DR GO; GO:0019087; P:transformation of host cell by virus; IMP:UniProtKB. DR InterPro; IPR000494; EGF_rcpt_L. DR InterPro; IPR008957; Fibronectin_typ-III-like_fold. DR InterPro; IPR003961; FN_III. DR InterPro; IPR006211; Furin-like. DR InterPro; IPR006212; Furin_repeat. DR InterPro; IPR016246; Insulin_rcpt. DR InterPro; IPR000719; Prot_kinase_core. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR002011; Recept_tyr_kinase-II_CS. DR InterPro; IPR001245; Tyr_pkinase. DR InterPro; IPR008266; Tyr_pkinase_AS. DR Gene3D; G3DSA:2.60.40.30; FN_III-like; 2. DR Pfam; PF00041; fn3; 2. DR Pfam; PF00757; Furin-like; 1. DR Pfam; PF07714; Pkinase_Tyr; 1. DR Pfam; PF01030; Recep_L_domain; 2. DR PIRSF; PIRSF000620; Insulin_receptor; 1. DR PRINTS; PR00109; TYRKINASE. DR ProDom; PD000001; Prot_kinase; 1. DR SMART; SM00060; FN3; 3. DR SMART; SM00261; FU; 2. DR SMART; SM00219; TyrKc; 1. DR PROSITE; PS50853; FN3; 3. 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; Acetylation; Alternative splicing; ATP-binding; KW Carbohydrate metabolism; Cleavage on pair of basic residues; KW Complete proteome; Diabetes mellitus; Direct protein sequencing; KW Disease mutation; Disulfide bond; Glycoprotein; Kinase; Membrane; KW Nucleotide-binding; Phosphoprotein; Polymorphism; Receptor; Repeat; KW Signal; Transferase; Transmembrane; Tyrosine-protein kinase. FT SIGNAL 1 27 FT CHAIN 28 758 Insulin receptor subunit alpha. FT /FTId=PRO_0000016687. FT CHAIN 763 1382 Insulin receptor subunit beta. FT /FTId=PRO_0000016689. FT TOPO_DOM 763 956 Extracellular (Potential). FT TRANSMEM 957 979 Potential. FT TOPO_DOM 980 1382 Cytoplasmic (Potential). FT DOMAIN 622 695 Fibronectin type-III 1. FT DOMAIN 757 842 Fibronectin type-III 2. FT DOMAIN 850 946 Fibronectin type-III 3. FT DOMAIN 1023 1298 Protein kinase. FT NP_BIND 1029 1037 ATP (By similarity). FT REGION 996 999 IRS1- and SHC1-binding. FT REGION 1361 1364 PIK3R1-binding. FT COMPBIAS 182 339 Cys-rich. FT ACT_SITE 1159 1159 Proton acceptor (By similarity). FT BINDING 1057 1057 ATP. FT SITE 996 996 Essential for IRS1-binding and important FT but not critical for SHC1-binding. FT SITE 997 997 Essential for IRS1-binding and important FT but not critical for SHC1-binding. FT SITE 999 999 Important for biological activity. FT MOD_RES 400 400 Phosphoserine. FT MOD_RES 401 401 Phosphotyrosine. FT MOD_RES 407 407 Phosphoserine. FT MOD_RES 992 992 Phosphotyrosine; by autocatalysis FT (Probable). FT MOD_RES 999 999 Phosphotyrosine; by autocatalysis. FT MOD_RES 1011 1011 Phosphotyrosine; by autocatalysis FT (Probable). FT MOD_RES 1112 1112 N6-acetyllysine. FT MOD_RES 1185 1185 Phosphotyrosine; by autocatalysis. FT MOD_RES 1189 1189 Phosphotyrosine; by autocatalysis. FT MOD_RES 1190 1190 Phosphotyrosine; by autocatalysis. FT MOD_RES 1354 1354 Phosphoserine. FT MOD_RES 1355 1355 Phosphotyrosine; by autocatalysis. FT MOD_RES 1361 1361 Phosphotyrosine; by autocatalysis. FT CARBOHYD 43 43 N-linked (GlcNAc...). FT CARBOHYD 52 52 N-linked (GlcNAc...) (Potential). FT CARBOHYD 105 105 N-linked (GlcNAc...) (Potential). FT CARBOHYD 138 138 N-linked (GlcNAc...) (Potential). FT CARBOHYD 242 242 N-linked (GlcNAc...). FT CARBOHYD 282 282 N-linked (GlcNAc...) (Potential). FT CARBOHYD 322 322 N-linked (GlcNAc...) (Potential). FT CARBOHYD 364 364 N-linked (GlcNAc...) (Potential). FT CARBOHYD 424 424 N-linked (GlcNAc...) (Potential). FT CARBOHYD 445 445 N-linked (GlcNAc...). FT CARBOHYD 541 541 N-linked (GlcNAc...). FT CARBOHYD 633 633 N-linked (GlcNAc...) (Potential). FT CARBOHYD 651 651 N-linked (GlcNAc...) (Potential). FT CARBOHYD 698 698 N-linked (GlcNAc...) (Potential). FT CARBOHYD 769 769 N-linked (GlcNAc...). FT CARBOHYD 782 782 N-linked (GlcNAc...) (Potential). FT CARBOHYD 920 920 N-linked (GlcNAc...). FT CARBOHYD 933 933 N-linked (GlcNAc...) (Potential). FT DISULFID 219 228 By similarity. FT DISULFID 223 234 By similarity. FT DISULFID 235 243 By similarity. FT DISULFID 239 252 By similarity. FT DISULFID 255 264 By similarity. FT DISULFID 268 280 By similarity. FT DISULFID 286 293 By similarity. FT DISULFID 301 311 By similarity. FT DISULFID 315 328 By similarity. FT DISULFID 331 335 By similarity. FT DISULFID 462 495 FT DISULFID 551 551 Interchain. FT VAR_SEQ 745 756 Missing (in isoform Short). FT /FTId=VSP_002898. FT VARIANT 2 2 G -> A (in dbSNP:rs7508518). FT /FTId=VAR_058395. FT VARIANT 42 42 N -> K (in RMS; impairs transport to the FT plasma membrane and reduces the affinity FT to bind insulin). FT /FTId=VAR_004079. FT VARIANT 55 55 V -> A (in leprechaunism; Verona-1). FT /FTId=VAR_004080. FT VARIANT 58 58 G -> R (in leprechaunism; Helmond; FT inhibits processing and transport; FT dbSNP:rs52836744). FT /FTId=VAR_004081. FT VARIANT 86 86 D -> G (in Ins resistance; type A). FT /FTId=VAR_015907. FT VARIANT 89 89 L -> P (in Ins resistance; type A). FT /FTId=VAR_015908. FT VARIANT 113 113 R -> P (in leprechaunism; Atlanta-1; FT abolishes insulin binding). FT /FTId=VAR_004082. FT VARIANT 119 119 A -> V (in leprechaunism; markedly FT impairs insulin binding). FT /FTId=VAR_015909. FT VARIANT 120 120 L -> Q (in leprechaunism; inhibits FT receptor processing). FT /FTId=VAR_031518. FT VARIANT 146 146 I -> M (in leprechaunism; mild). FT /FTId=VAR_015539. FT VARIANT 167 167 V -> L (in Ins resistance; type A). FT /FTId=VAR_015910. FT VARIANT 171 171 Y -> H (in dbSNP:rs1051692). FT /FTId=VAR_058396. FT VARIANT 220 220 P -> L (in Ins resistance; severe). FT /FTId=VAR_004083. FT VARIANT 228 228 C -> R (in a gastric adenocarcinoma FT sample; somatic mutation). FT /FTId=VAR_041429. FT VARIANT 236 236 H -> R (in leprechaunism; Winnipeg; in FT one patient with in RMS heterozygous FT compound with S-386; may impair receptor FT processing). FT /FTId=VAR_004084. FT VARIANT 260 260 L -> P (in leprechaunism; Geldeimalsen). FT /FTId=VAR_004085. FT VARIANT 279 279 R -> C (in Ins resistance; severe; FT inhibits receptor internalization). FT /FTId=VAR_015540. FT VARIANT 279 279 R -> H (in IRAN type A; interferes with FT receptor processing). FT /FTId=VAR_031519. FT VARIANT 280 280 C -> Y (in Ins resistance; type A). FT /FTId=VAR_015911. FT VARIANT 301 301 C -> Y (in leprechaunism). FT /FTId=VAR_015912. FT VARIANT 308 308 Missing (in leprechaunism; abolishes FT insulin binding). FT /FTId=VAR_015913. FT VARIANT 350 350 S -> L (in RMS and leprechaunism). FT /FTId=VAR_015914. FT VARIANT 362 362 Missing (in leprechaunism). FT /FTId=VAR_015541. FT VARIANT 386 386 G -> S (in RMS; may impair receptor FT processing). FT /FTId=VAR_031520. FT VARIANT 393 393 G -> R (in leprechaunism; Verona-1). FT /FTId=VAR_004086. FT VARIANT 409 409 F -> V (in Ins resistance; severe). FT /FTId=VAR_004087. FT VARIANT 439 439 W -> S (in leprechaunism; impairs FT transport of the receptor to the cell FT surface). FT /FTId=VAR_015542. FT VARIANT 448 448 I -> T (in dbSNP:rs1051691). FT /FTId=VAR_015915. FT VARIANT 458 458 N -> D (in leprechaunism; partially FT inhibits receptor processing and FT autophosphorylation; strongly impairs ERK FT phosphorylation; induces wild-type levels FT of IRS-1 phosphorylation). FT /FTId=VAR_031521. FT VARIANT 487 487 K -> E (in leprechaunism; ARK-1). FT /FTId=VAR_004088. FT VARIANT 489 489 N -> S (in IRAN type A). FT /FTId=VAR_004089. FT VARIANT 492 492 Q -> K (in dbSNP:rs1131851). FT /FTId=VAR_015916. FT VARIANT 695 695 Q -> R (in dbSNP:rs55906835). FT /FTId=VAR_041430. FT VARIANT 762 762 R -> S (in IRAN type A). FT /FTId=VAR_004090. FT VARIANT 811 811 G -> S (in dbSNP:rs35045353). FT /FTId=VAR_041431. FT VARIANT 830 830 P -> L (in dbSNP:rs2162771). FT /FTId=VAR_055986. FT VARIANT 858 858 T -> A (in NIDDM). FT /FTId=VAR_015917. FT VARIANT 925 925 I -> T (in leprechaunism; abolishes FT insulin binding). FT /FTId=VAR_015918. FT VARIANT 926 926 R -> W (in leprechaunism; markedly FT impairs insulin binding). FT /FTId=VAR_015919. FT VARIANT 937 937 T -> M (in leprechaunism; impaired FT receptor processing). FT /FTId=VAR_015920. FT VARIANT 997 997 P -> T (in RMS; reduces insulin binding). FT /FTId=VAR_015921. FT VARIANT 1012 1012 V -> M (rare polymorphism; FT dbSNP:rs1799816). FT /FTId=VAR_004091. FT VARIANT 1020 1020 R -> Q (in IRAN type A). FT /FTId=VAR_004092. FT VARIANT 1023 1023 I -> F. FT /FTId=VAR_015922. FT VARIANT 1035 1035 G -> V (in IRAN type A). FT /FTId=VAR_004093. FT VARIANT 1055 1055 A -> V (in Ins resistance; type A). FT /FTId=VAR_015923. FT VARIANT 1065 1065 L -> V (in dbSNP:rs56395521). FT /FTId=VAR_041432. FT VARIANT 1075 1075 A -> D (in Ins resistance; type A). FT /FTId=VAR_004094. FT VARIANT 1095 1095 K -> E (in a NIDDM subject). FT /FTId=VAR_015924. FT VARIANT 1119 1119 R -> W (in leprechaunism). FT /FTId=VAR_015925. FT VARIANT 1143 1143 I -> T (in RMS; reduces insulin binding). FT /FTId=VAR_015926. FT VARIANT 1158 1158 R -> Q (in Ins resistance). FT /FTId=VAR_015927. FT VARIANT 1158 1158 R -> W (in RMS; abolishes insulin FT binding). FT /FTId=VAR_015928. FT VARIANT 1161 1161 A -> T (in IRAN type A). FT /FTId=VAR_004095. FT VARIANT 1162 1162 A -> E (in IRAN type A; impairs FT proteolytic processing). FT /FTId=VAR_004096. FT VARIANT 1180 1180 M -> I (in Ins resistance). FT /FTId=VAR_004097. FT VARIANT 1191 1191 R -> Q (in NIDDM). FT /FTId=VAR_004098. FT VARIANT 1201 1201 R -> Q (in HHF5 and IRAN type A; FT interferes with kinase activation by FT insulin). FT /FTId=VAR_015929. FT VARIANT 1201 1201 R -> W (in leprechaunism and RMS; reduces FT insulin binding possibly due to reduced FT receptor levels on the cell surface). FT /FTId=VAR_015930. FT VARIANT 1205 1205 P -> L (in Ins resistance; type A; FT moderate). FT /FTId=VAR_004099. FT VARIANT 1206 1206 E -> D (in Ins resistance; type A; FT accelerates degradation of the protein FT and impairs kinase activity). FT /FTId=VAR_015931. FT VARIANT 1206 1206 E -> K (in leprechaunism). FT /FTId=VAR_015932. FT VARIANT 1220 1220 W -> L (in Ins resistance; type A; FT accelerates degradation of the protein FT and impairs kinase activity; FT dbSNP:rs52800171). FT /FTId=VAR_004100. FT VARIANT 1227 1227 W -> S (in IRAN type A). FT /FTId=VAR_004101. FT VARIANT 1282 1282 T -> A (in dbSNP:rs55875349). FT /FTId=VAR_041433. FT VARIANT 1361 1361 Y -> C (in dbSNP:rs13306449). FT /FTId=VAR_015933. FT VARIANT 1378 1378 R -> Q (in Ins resistance; type A; FT dbSNP:rs52826008). FT /FTId=VAR_015934. FT MUTAGEN 991 991 L->A: Reduces interaction with IRS1 but FT has no effect on interaction with SHC1. FT MUTAGEN 992 992 Y->A: Reduces interaction with IRS1 but FT has no effect on interaction with SHC1. FT MUTAGEN 996 997 NP->AA: Abolishes interaction with IRS1. FT Severely disrupts, but does not abolish FT interaction with SHC1. FT MUTAGEN 996 996 N->A: Abolishes interaction with IRS1 and FT significantly reduces interaction with FT SHC1. Has no effect on interaction with FT PIK3R1. FT MUTAGEN 997 997 P->A: Abolishes interaction with IRS1 and FT significantly reduces interaction with FT SHC1. Has no effect on interaction with FT PIK3R1. FT MUTAGEN 998 998 E->A: Does not affect interaction with FT IRS1, SHC1 or PIK3R1. FT MUTAGEN 999 999 Y->E: Abolishes interaction with IRS1 and FT SHC1. FT MUTAGEN 999 999 Y->F: Has no effect on insulin-stimulated FT autophosphorylation, but inhibits the FT biological activity of the receptor. FT Abolishes interaction with IRS1 and FT almost completely prevents interaction FT with SHC1. Has no effect on interaction FT with PIK3R1. FT MUTAGEN 1000 1000 L->A,R: Severely reduces interaction with FT SHC1. Has no effect on interaction with FT IRS1. FT MUTAGEN 1002 1002 A->D: Reduces interaction with IRS1 but FT has no effect on interaction with SHC1. FT MUTAGEN 1057 1057 K->A: Abolishes the kinase activity and FT abolishes interaction with IRS1, SHC1 and FT PIK3R1. FT MUTAGEN 1057 1057 K->M,R: Abolishes the kinase activity. FT CONFLICT 601 601 D -> N (in Ref. 19; AA sequence). FT CONFLICT 830 830 P -> E (in Ref. 19; AA sequence). FT CONFLICT 1278 1278 K -> N (in Ref. 2; CAA26096). FT STRAND 33 42 FT HELIX 45 50 FT STRAND 53 65 FT HELIX 70 72 FT TURN 73 75 FT STRAND 83 86 FT STRAND 88 93 FT TURN 100 102 FT STRAND 118 124 FT STRAND 141 149 FT HELIX 160 162 FT STRAND 171 175 FT HELIX 176 178 FT TURN 187 192 FT STRAND 199 201 FT STRAND 204 206 FT STRAND 209 211 FT HELIX 221 223 FT STRAND 243 247 FT STRAND 251 260 FT STRAND 263 267 FT STRAND 273 275 FT TURN 276 278 FT STRAND 279 281 FT HELIX 283 295 FT STRAND 298 300 FT STRAND 305 307 FT STRAND 310 314 FT STRAND 319 321 FT STRAND 327 330 FT STRAND 332 334 FT STRAND 338 348 FT HELIX 351 355 FT TURN 356 359 FT STRAND 361 369 FT HELIX 377 385 FT STRAND 390 393 FT STRAND 395 399 FT STRAND 404 406 FT TURN 422 424 FT STRAND 425 430 FT TURN 441 443 FT STRAND 452 458 FT HELIX 463 472 FT TURN 476 478 FT TURN 481 483 FT STRAND 486 490 FT STRAND 513 515 FT STRAND 521 523 FT STRAND 527 530 FT STRAND 534 536 FT TURN 539 541 FT STRAND 564 567 FT STRAND 572 574 FT STRAND 577 580 FT STRAND 591 595 FT STRAND 626 632 FT STRAND 634 636 FT STRAND 638 643 FT STRAND 648 651 FT STRAND 653 656 FT STRAND 659 662 FT STRAND 672 674 FT STRAND 805 809 FT STRAND 817 820 FT STRAND 823 826 FT STRAND 828 831 FT STRAND 840 843 FT STRAND 861 865 FT STRAND 881 884 FT STRAND 889 893 FT STRAND 902 904 FT STRAND 918 921 FT STRAND 927 929 FT TURN 1014 1016 FT HELIX 1020 1022 FT STRAND 1023 1031 FT STRAND 1033 1043 FT STRAND 1050 1058 FT HELIX 1065 1078 FT STRAND 1089 1093 FT STRAND 1095 1098 FT STRAND 1100 1104 FT HELIX 1111 1117 FT HELIX 1133 1152 FT HELIX 1162 1164 FT STRAND 1165 1167 FT STRAND 1173 1175 FT HELIX 1200 1202 FT HELIX 1205 1210 FT HELIX 1215 1230 FT TURN 1236 1239 FT HELIX 1242 1250 FT HELIX 1263 1272 FT HELIX 1277 1279 FT HELIX 1283 1290 FT HELIX 1291 1293 FT HELIX 1298 1301 FT HELIX 1307 1309 SQ SEQUENCE 1382 AA; 156319 MW; D57E03CC3E3CDA62 CRC64; MGTGGRRGAA 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 //