Insulin receptor (IR) (EC 2 7 10 1) (CD antigen CD220) [Cleaved into: Insulin receptor subunit alpha; Insulin receptor subunit beta]

 INSR_RAT                Reviewed;        1383 AA.
 P15127; P97681;
 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
 01-APR-1990, sequence version 1.
 10-FEB-2021, entry version 201.
 RecName: Full=Insulin receptor;
          Short=IR;
          EC=2.7.10.1;
 AltName: CD_antigen=CD220;
 Contains:
   RecName: Full=Insulin receptor subunit alpha;
 Contains:
   RecName: Full=Insulin receptor subunit beta;
 Flags: Precursor;
 Name=Insr;
 Rattus norvegicus (Rat).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
 Murinae; Rattus.
 NCBI_TaxID=10116;
 [1]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND ALTERNATIVE SPLICING
 (ISOFORM SHORT).
 PubMed=2330003; DOI=10.1210/mend-4-2-235;
 Goldstein B.J., Dudley A.L.;
 "The rat insulin receptor: primary structure and conservation of tissue-
 specific alternative messenger RNA splicing.";
 Mol. Endocrinol. 4:235-244(1990).
 [2]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 731-756; 758-819; 969-994 AND
 1119-1177.
 STRAIN=Sprague-Dawley;
 Liu Y., Tam J.W.O.;
 Submitted (MAY-1997) to the EMBL/GenBank/DDBJ databases.
 [3]
 INTERACTION WITH GRB7.
 PubMed=10803466; DOI=10.1038/sj.onc.1203469;
 Kasus-Jacobi A., Bereziat V., Perdereau D., Girard J., Burnol A.F.;
 "Evidence for an interaction between the insulin receptor and Grb7. A role
 for two of its binding domains, PIR and SH2.";
 Oncogene 19:2052-2059(2000).
 [4]
 FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R.
 PubMed=16803852; DOI=10.1152/ajpendo.00565.2005;
 Johansson G.S., Arnqvist H.J.;
 "Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid
 insulin/IGF-I receptors in vascular smooth muscle cells.";
 Am. J. Physiol. 291:E1124-E1130(2006).
 [5]
 INTERACTION WITH CAV2.
 PubMed=19778377; DOI=10.1111/j.1582-4934.2009.00391.x;
 Kwon H., Jeong K., Pak Y.;
 "Identification of pY19-caveolin-2 as a positive regulator of insulin-
 stimulated actin cytoskeleton-dependent mitogenesis.";
 J. Cell. Mol. Med. 13:1549-1564(2009).
 [6]
 INTERACTION WITH CCDC88A AND GNAI3.
 PubMed=25187647; DOI=10.1091/mbc.e14-05-0978;
 Lin C., Ear J., Midde K., Lopez-Sanchez I., Aznar N., Garcia-Marcos M.,
 Kufareva I., Abagyan R., Ghosh P.;
 "Structural basis for activation of trimeric Gi proteins by multiple growth
 factor receptors via GIV/Girdin.";
 Mol. Biol. Cell 25:3654-3671(2014).
 [7]
 INTERACTION WITH ATIC.
 PubMed=25687571; DOI=10.1074/mcp.m114.047159;
 Boutchueng-Djidjou M., Collard-Simard G., Fortier S., Hebert S.S.,
 Kelly I., Landry C.R., Faure R.L.;
 "The last enzyme of the de novo purine synthesis pathway 5-aminoimidazole-
 4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC)
 plays a central role in insulin signaling and the Golgi/endosomes protein
 network.";
 Mol. Cell. Proteomics 14:1079-1092(2015).
 -!- FUNCTION: Receptor tyrosine kinase which mediates the pleiotropic
     actions of insulin. Binding of insulin leads to phosphorylation of
     several intracellular substrates, including, insulin receptor
     substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling
     intermediates. Each of these phosphorylated proteins serve as docking
     proteins for other signaling proteins that contain Src-homology-2
     domains (SH2 domain) that specifically recognize different
     phosphotyrosine residues, including the p85 regulatory subunit of PI3K
     and SHP2. Phosphorylation of IRSs proteins lead to the activation of
     two main signaling pathways: the PI3K-AKT/PKB pathway, which is
     responsible for most of the metabolic actions of insulin, and the Ras-
     MAPK pathway, which regulates expression of some genes and cooperates
     with the PI3K pathway to control cell growth and differentiation.
     Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to
     the activation of PI3K and the generation of phosphatidylinositol-(3,
     4, 5)-triphosphate (PIP3), a lipid second messenger, which activates
     several PIP3-dependent serine/threonine kinases, such as PDPK1 and
     subsequently AKT/PKB. The net effect of this pathway is to produce a
     translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic
     vesicles to the cell membrane to facilitate glucose transport.
     Moreover, upon insulin stimulation, activated AKT/PKB is responsible
     for: anti-apoptotic effect of insulin by inducing phosphorylation of
     BAD; regulates the expression of gluconeogenic and lipogenic enzymes by
     controlling the activity of the winged helix or forkhead (FOX) class of
     transcription factors. Another pathway regulated by PI3K-AKT/PKB
     activation is mTORC1 signaling pathway which regulates cell growth and
     metabolism and integrates signals from insulin. AKT mediates insulin-
     stimulated protein synthesis by phosphorylating TSC2 thereby activating
     mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in
     mediating cell growth, survival and cellular differentiation of
     insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers
     the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to
     binding insulin, the insulin receptor can bind insulin-like growth
     factors (IGFI and IGFII). When present in a hybrid receptor with IGF1R,
     binds IGF1 (By similarity). In adipocytes, inhibits lipolysis (By
     similarity). {ECO:0000250, ECO:0000250|UniProtKB:P15208,
     ECO:0000269|PubMed:16803852}.
 -!- CATALYTIC ACTIVITY:
     Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
       [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
       COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
       ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
       Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
 -!- ACTIVITY REGULATION: Activated in response to insulin.
     Autophosphorylation activates the kinase activity. PTPN1, PTPRE and
     PTPRF dephosphorylate important tyrosine residues, thereby reducing
     INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the
     catalytic activity of the INSR, they block access of substrates to the
     activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR
     activity, they bind to the activated INRS and interfere with the
     phosphorylation of INSR substrates (By similarity). {ECO:0000250}.
 -!- SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide
     bonds. The alpha chains carry the insulin-binding regions, while the
     beta chains carry the kinase domain. Forms a hybrid receptor with
     IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta
     chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts
     with SORBS1 but dissociates from it following insulin stimulation.
     Binds SH2B2. Activated form of INSR interacts (via Tyr-1000) with the
     PTB/PID domains of IRS1 and SHC1. The sequences surrounding the
     phosphorylated NPXY motif contribute differentially to either IRS1 or
     SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2
     (via PTB domain and 591-786 AA); the 591-786 would be the primary
     anchor of IRS2 to INSR while the PTB domain would have a stabilizing
     action on the interaction with INSR. Interacts with the SH2 domains of
     the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when
     autophosphorylated on tyrosine residues. Interacts with SOCS7.
     Interacts (via the phosphorylated Tyr-1000), with SOCS3. Interacts (via
     the phosphorylated Tyr-1186, Tyr-1190, Tyr-1191) with SOCS1. Interacts
     with ARRB2 (By similarity). Interacts with GRB10; this interaction
     blocks the association between IRS1/IRS2 and INSR, significantly
     reduces insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2
     and thus decreases insulin signaling. Interacts with PDPK1. Interacts
     (via Tyr-1191) with GRB14 (via BPS domain); this interaction protects
     the tyrosines in the activation loop from dephosphorylation, but
     promotes dephosphorylation of Tyr-1000, this results in decreased
     interaction with, and phosphorylation of, IRS1. Interacts (via subunit
     alpha) with ENPP1 (via 485-599 AA); this interaction blocks
     autophosphorylation. Interacts with PTPRE; this interaction is
     dependent of Tyr-1186, Tyr-1190 and Tyr-1191 of the INSR. Interacts
     with STAT5B (via SH2 domain). Interacts with PTPRF (By similarity).
     Interacts with GRB7. Interacts with CAV2 (tyrosine-phosphorylated
     form); the interaction is increased with 'Tyr-27'phosphorylation of
     CAV2. Interacts with ATIC; ATIC together with PRKAA2/AMPK2 and
     HACD3/PTPLAD1 is proposed to be part of a signaling netwok regulating
     INSR autophosphorylation and endocytosis (PubMed:25687571). Interacts
     with the insulin receptor SORL1; this interaction strongly increases
     its surface exposure, hence strengthens insulin signal reception (By
     similarity). Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via
     SH2-like region); binding requires autophosphorylation of the INSR C-
     terminal region (PubMed:25187647). Interacts with GNAI3; the
     interaction is probably mediated by CCDC88A/GIV (PubMed:25187647).
     {ECO:0000250, ECO:0000250|UniProtKB:P15208,
     ECO:0000269|PubMed:10803466, ECO:0000269|PubMed:19778377,
     ECO:0000269|PubMed:25187647, ECO:0000269|PubMed:25687571}.
 -!- INTERACTION:
     P15127; Q62689: Jak2; NbExp=2; IntAct=EBI-7472166, EBI-8656708;
     PRO_0000016698; O35567: Atic; NbExp=3; IntAct=EBI-10768746, EBI-10768817;
 -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P15208};
     Single-pass type I membrane protein {ECO:0000305}. Late endosome
     {ECO:0000250|UniProtKB:P15208}. Lysosome
     {ECO:0000250|UniProtKB:P15208}. Note=Binding of insulin to INSR induces
     internalization and lysosomal degradation of the receptor, a means for
     downregulating this signaling pathway after stimulation. In the
     presence of SORL1, internalized INSR molecules are redirected back to
     the cell surface, thereby preventing their lysosomal catabolism and
     strengthening insulin signal reception. {ECO:0000250|UniProtKB:P15208}.
 -!- ALTERNATIVE PRODUCTS:
     Event=Alternative splicing; Named isoforms=2;
     Name=Long; Synonyms=RIR-B;
       IsoId=P15127-1; Sequence=Displayed;
     Name=Short; Synonyms=RIR-A;
       IsoId=P15127-2; Sequence=VSP_036680;
 -!- DOMAIN: The tetrameric insulin receptor binds insulin via non-identical
     regions from two alpha chains, primarily via the C-terminal region of
     the first INSR alpha chain. Residues from the leucine-rich N-terminus
     of the other INSR alpha chain also contribute to this insulin binding
     site. A secondary insulin-binding site is formed by residues at the
     junction of fibronectin type-III domain 1 and 2 (By similarity).
     {ECO:0000250}.
 -!- PTM: Autophosphorylated on tyrosine residues in response to insulin.
     Phosphorylation of Tyr-1000 is required for binding to IRS1, SHC1, and
     STAT5B. Dephosphorylated by PTPRE on Tyr-1000, Tyr-1186, Tyr-1190 and
     Tyr-1191 residues. Dephosphorylated by PTPRF and PTPN1.
     Dephosphorylated by PTPN2; down-regulates insulin-induced signaling.
     {ECO:0000250}.
 -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
     kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
     ProRule:PRU00159}.
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 EMBL; M29014; AAA41441.1; -; mRNA.
 EMBL; AF005776; AAB61414.1; -; Genomic_DNA.
 EMBL; AF005777; AAB61415.1; -; Genomic_DNA.
 EMBL; AH004882; AAB38967.1; -; Genomic_DNA.
 EMBL; AH004883; AAB38968.1; -; Genomic_DNA.
 EMBL; U80633; AAB38746.1; -; Genomic_DNA.
 PIR; A36080; A36080.
 PDB; 4XST; X-ray; 3.00 A; F=726-748.
 PDB; 5TQ1; X-ray; 1.49 A; B=1008-1018.
 PDBsum; 4XST; -.
 PDBsum; 5TQ1; -.
 BMRB; P15127; -.
 SMR; P15127; -.
 DIP; DIP-42209N; -.
 IntAct; P15127; 460.
 MINT; P15127; -.
 STRING; 10116.ENSRNOP00000060141; -.
 BindingDB; P15127; -.
 ChEMBL; CHEMBL5486; -.
 DrugCentral; P15127; -.
 GlyGen; P15127; 18 sites, 5 N-linked glycans (1 site).
 iPTMnet; P15127; -.
 PhosphoSitePlus; P15127; -.
 PaxDb; P15127; -.
 PeptideAtlas; P15127; -.
 PRIDE; P15127; -.
 UCSC; RGD:2917; rat. [P15127-1]
 RGD; 2917; Insr.
 eggNOG; KOG4258; Eukaryota.
 InParanoid; P15127; -.
 PhylomeDB; P15127; -.
 BRENDA; 2.7.10.1; 5301.
 Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
 Reactome; R-RNO-74713; IRS activation.
 Reactome; R-RNO-74749; Signal attenuation.
 Reactome; R-RNO-74751; Insulin receptor signalling cascade.
 Reactome; R-RNO-74752; Signaling by Insulin receptor.
 Reactome; R-RNO-77387; Insulin receptor recycling.
 PRO; PR:P15127; -.
 Proteomes; UP000002494; Unplaced.
 GO; GO:0030424; C:axon; IBA:GO_Central.
 GO; GO:0005901; C:caveola; ISO:RGD.
 GO; GO:0031410; C:cytoplasmic vesicle; IDA:RGD.
 GO; GO:0005829; C:cytosol; IDA:RGD.
 GO; GO:0032590; C:dendrite membrane; IDA:ARUK-UCL.
 GO; GO:0005768; C:endosome; IDA:RGD.
 GO; GO:0009897; C:external side of plasma membrane; IDA:ARUK-UCL.
 GO; GO:0005899; C:insulin receptor complex; ISO:RGD.
 GO; GO:0005887; C:integral component of plasma membrane; ISO:RGD.
 GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
 GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell.
 GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
 GO; GO:0016020; C:membrane; ISO:RGD.
 GO; GO:0043025; C:neuronal cell body; IDA:RGD.
 GO; GO:0032809; C:neuronal cell body membrane; IDA:ARUK-UCL.
 GO; GO:0005634; C:nucleus; IDA:RGD.
 GO; GO:0005886; C:plasma membrane; IDA:RGD.
 GO; GO:0043235; C:receptor complex; ISO:RGD.
 GO; GO:0045202; C:synapse; IDA:RGD.
 GO; GO:0060417; C:yolk; IDA:RGD.
 GO; GO:0043423; F:3-phosphoinositide-dependent protein kinase binding; IDA:RGD.
 GO; GO:0001540; F:amyloid-beta binding; ISO:RGD.
 GO; GO:0005524; F:ATP binding; ISO:RGD.
 GO; GO:0038024; F:cargo receptor activity; IMP:ARUK-UCL.
 GO; GO:0005525; F:GTP binding; ISO:RGD.
 GO; GO:0042802; F:identical protein binding; ISO:RGD.
 GO; GO:0043559; F:insulin binding; IDA:RGD.
 GO; GO:0043560; F:insulin receptor substrate binding; IMP:RGD.
 GO; GO:0005009; F:insulin-activated receptor activity; IDA:RGD.
 GO; GO:0031994; F:insulin-like growth factor I binding; ISO:RGD.
 GO; GO:0031995; F:insulin-like growth factor II binding; ISO:RGD.
 GO; GO:0005159; F:insulin-like growth factor receptor binding; ISO:RGD.
 GO; GO:0031405; F:lipoic acid binding; IPI:RGD.
 GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; ISO:RGD.
 GO; GO:0019904; F:protein domain specific binding; IPI:RGD.
 GO; GO:0004672; F:protein kinase activity; IDA:RGD.
 GO; GO:0019901; F:protein kinase binding; IPI:RGD.
 GO; GO:0019903; F:protein phosphatase binding; IMP:RGD.
 GO; GO:0004713; F:protein tyrosine kinase activity; IDA:RGD.
 GO; GO:0044877; F:protein-containing complex binding; IPI:RGD.
 GO; GO:0051425; F:PTB domain binding; ISO:RGD.
 GO; GO:0005198; F:structural molecule activity; ISO:RGD.
 GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
 GO; GO:0000187; P:activation of MAPK activity; ISO:RGD.
 GO; GO:0032147; P:activation of protein kinase activity; ISO:RGD.
 GO; GO:0032148; P:activation of protein kinase B activity; ISO:RGD.
 GO; GO:0030325; P:adrenal gland development; ISO:RGD.
 GO; GO:0000380; P:alternative mRNA splicing, via spliceosome; IEP:RGD.
 GO; GO:0097242; P:amyloid-beta clearance; IMP:ARUK-UCL.
 GO; GO:0009887; P:animal organ morphogenesis; ISO:RGD.
 GO; GO:0071363; P:cellular response to growth factor stimulus; ISO:RGD.
 GO; GO:0032869; P:cellular response to insulin stimulus; ISO:RGD.
 GO; GO:0021549; P:cerebellum development; IEP:RGD.
 GO; GO:0097062; P:dendritic spine maintenance; IGI:ARUK-UCL.
 GO; GO:1990402; P:embryonic liver development; IEP:RGD.
 GO; GO:0008544; P:epidermis development; ISO:RGD.
 GO; GO:0031017; P:exocrine pancreas development; ISO:RGD.
 GO; GO:0045444; P:fat cell differentiation; IEP:RGD.
 GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISO:RGD.
 GO; GO:0042593; P:glucose homeostasis; IDA:RGD.
 GO; GO:0003007; P:heart morphogenesis; ISO:RGD.
 GO; GO:0021766; P:hippocampus development; IEP:RGD.
 GO; GO:0008286; P:insulin receptor signaling pathway; IDA:RGD.
 GO; GO:0001889; P:liver development; IEP:RGD.
 GO; GO:0097421; P:liver regeneration; IEP:RGD.
 GO; GO:0008584; P:male gonad development; ISO:RGD.
 GO; GO:0030238; P:male sex determination; ISO:RGD.
 GO; GO:0007275; P:multicellular organism development; IBA:GO_Central.
 GO; GO:2000252; P:negative regulation of feeding behavior; IMP:RGD.
 GO; GO:0010629; P:negative regulation of gene expression; IMP:RGD.
 GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; IEP:RGD.
 GO; GO:0001933; P:negative regulation of protein phosphorylation; IMP:RGD.
 GO; GO:0032410; P:negative regulation of transporter activity; IMP:RGD.
 GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL.
 GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; ISO:RGD.
 GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IMP:RGD.
 GO; GO:0030335; P:positive regulation of cell migration; ISO:RGD.
 GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD.
 GO; GO:0048639; P:positive regulation of developmental growth; ISO:RGD.
 GO; GO:0046326; P:positive regulation of glucose import; ISO:RGD.
 GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; ISO:RGD.
 GO; GO:0045821; P:positive regulation of glycolytic process; ISO:RGD.
 GO; GO:0010560; P:positive regulation of glycoprotein biosynthetic process; IMP:RGD.
 GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
 GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:RGD.
 GO; GO:0051446; P:positive regulation of meiotic cell cycle; ISO:RGD.
 GO; GO:0045840; P:positive regulation of mitotic nuclear division; ISO:RGD.
 GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; ISO:RGD.
 GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IBA:GO_Central.
 GO; GO:0042327; P:positive regulation of phosphorylation; IDA:BHF-UCL.
 GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISO:RGD.
 GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:RGD.
 GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; IGI:ARUK-UCL.
 GO; GO:0002092; P:positive regulation of receptor internalization; ISO:RGD.
 GO; GO:0060267; P:positive regulation of respiratory burst; ISO:RGD.
 GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:RGD.
 GO; GO:0046777; P:protein autophosphorylation; IDA:RGD.
 GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
 GO; GO:0006898; P:receptor-mediated endocytosis; IMP:ARUK-UCL.
 GO; GO:0045995; P:regulation of embryonic development; ISO:RGD.
 GO; GO:2000194; P:regulation of female gonad development; ISO:RGD.
 GO; GO:0006111; P:regulation of gluconeogenesis; IEP:RGD.
 GO; GO:0010310; P:regulation of hydrogen peroxide metabolic process; IDA:RGD.
 GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:RGD.
 GO; GO:0014823; P:response to activity; IEP:RGD.
 GO; GO:0032355; P:response to estradiol; IEP:RGD.
 GO; GO:0045471; P:response to ethanol; IEP:RGD.
 GO; GO:0032094; P:response to food; IEP:RGD.
 GO; GO:0051384; P:response to glucocorticoid; IEP:RGD.
 GO; GO:0009749; P:response to glucose; IEP:BHF-UCL.
 GO; GO:0009725; P:response to hormone; IEP:RGD.
 GO; GO:0001666; P:response to hypoxia; IEP:RGD.
 GO; GO:0032868; P:response to insulin; IEP:BHF-UCL.
 GO; GO:0010042; P:response to manganese ion; IEP:RGD.
 GO; GO:0031667; P:response to nutrient levels; IDA:RGD.
 GO; GO:0010033; P:response to organic substance; IEP:RGD.
 GO; GO:1904638; P:response to resveratrol; IEP:RGD.
 GO; GO:0033574; P:response to testosterone; IEP:RGD.
 GO; GO:0034612; P:response to tumor necrosis factor; IMP:RGD.
 GO; GO:1902438; P:response to vanadate(3-); IEP:RGD.
 GO; GO:0033280; P:response to vitamin D; IEP:RGD.
 GO; GO:0019087; P:transformation of host cell by virus; ISO:RGD.
 GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
 CDD; cd00063; FN3; 2.
 CDD; cd00064; FU; 1.
 Gene3D; 2.60.40.10; -; 2.
 Gene3D; 3.80.20.20; -; 2.
 InterPro; IPR003961; FN3_dom.
 InterPro; IPR036116; FN3_sf.
 InterPro; IPR006211; Furin-like_Cys-rich_dom.
 InterPro; IPR006212; Furin_repeat.
 InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
 InterPro; IPR013783; Ig-like_fold.
 InterPro; IPR040969; Insulin_TMD.
 InterPro; IPR011009; Kinase-like_dom_sf.
 InterPro; IPR000719; Prot_kinase_dom.
 InterPro; IPR017441; Protein_kinase_ATP_BS.
 InterPro; IPR000494; Rcpt_L-dom.
 InterPro; IPR036941; Rcpt_L-dom_sf.
 InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
 InterPro; IPR008266; Tyr_kinase_AS.
 InterPro; IPR020635; Tyr_kinase_cat_dom.
 InterPro; IPR016246; Tyr_kinase_insulin-like_rcpt.
 InterPro; IPR002011; Tyr_kinase_rcpt_2_CS.
 Pfam; PF00041; fn3; 1.
 Pfam; PF00757; Furin-like; 1.
 Pfam; PF17870; Insulin_TMD; 1.
 Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
 Pfam; PF01030; Recep_L_domain; 2.
 PIRSF; PIRSF000620; Insulin_receptor; 1.
 PRINTS; PR00109; TYRKINASE.
 SMART; SM00060; FN3; 3.
 SMART; SM00261; FU; 1.
 SMART; SM00219; TyrKc; 1.
 SUPFAM; SSF49265; SSF49265; 3.
 SUPFAM; SSF56112; SSF56112; 1.
 SUPFAM; SSF57184; SSF57184; 1.
 PROSITE; PS50853; FN3; 3.
 PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
 PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
 PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
 PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1.
 1: Evidence at protein level;
 3D-structure; Alternative splicing; ATP-binding; Cell membrane;
 Cleavage on pair of basic residues; Disulfide bond; Endosome; Glycoprotein;
 Kinase; Lysosome; Membrane; Nucleotide-binding; Phosphoprotein; Receptor;
 Reference proteome; Repeat; Signal; Transferase; Transmembrane;
 Transmembrane helix; Tyrosine-protein kinase.
 SIGNAL          1..26
 CHAIN           27..759
                 /note="Insulin receptor subunit alpha"
                 /id="PRO_0000016696"
 CHAIN           764..1383
                 /note="Insulin receptor subunit beta"
                 /id="PRO_0000016698"
 TOPO_DOM        27..759
                 /note="Extracellular"
                 /evidence="ECO:0000305"
 TOPO_DOM        764..957
                 /note="Extracellular"
                 /evidence="ECO:0000305"
 TRANSMEM        958..978
                 /note="Helical"
                 /evidence="ECO:0000255"
 TOPO_DOM        979..1383
                 /note="Cytoplasmic"
                 /evidence="ECO:0000305"
 DOMAIN          625..727
                 /note="Fibronectin type-III 1"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
 DOMAIN          754..848
                 /note="Fibronectin type-III 2"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
 DOMAIN          854..948
                 /note="Fibronectin type-III 3"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
 DOMAIN          1024..1299
                 /note="Protein kinase"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 NP_BIND         1105..1111
                 /note="ATP"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 NP_BIND         1164..1165
                 /note="ATP"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 REGION          734..742
                 /note="Insulin-binding"
                 /evidence="ECO:0000250"
 REGION          997..1000
                 /note="Important for interaction with IRS1, SHC1 and
                 STAT5B"
 REGION          1362..1365
                 /note="PIK3R1 binding"
                 /evidence="ECO:0000250"
 COMPBIAS        27..173
                 /note="Leu-rich"
 ACT_SITE        1160
                 /note="Proton donor/acceptor"
                 /evidence="ECO:0000250"
 BINDING         1034
                 /note="ATP"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 BINDING         1058
                 /note="ATP"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 BINDING         1178
                 /note="ATP"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 SITE            65
                 /note="Insulin-binding"
                 /evidence="ECO:0000250"
 MOD_RES         399
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 MOD_RES         400
                 /note="Phosphotyrosine"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 MOD_RES         406
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 MOD_RES         1000
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 MOD_RES         1186
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 MOD_RES         1190
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 MOD_RES         1191
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 MOD_RES         1356
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 MOD_RES         1362
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P06213"
 CARBOHYD        42
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        51
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        104
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        137
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        241
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        281
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        321
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        363
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        423
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        444
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        540
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        634
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        652
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        699
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        770
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        783
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        921
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        934
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 DISULFID        34..52
                 /evidence="ECO:0000250"
 DISULFID        152..181
                 /evidence="ECO:0000250"
 DISULFID        185..208
                 /evidence="ECO:0000250"
 DISULFID        195..214
                 /evidence="ECO:0000250"
 DISULFID        218..227
                 /evidence="ECO:0000250"
 DISULFID        222..233
                 /evidence="ECO:0000250"
 DISULFID        234..242
                 /evidence="ECO:0000250"
 DISULFID        238..251
                 /evidence="ECO:0000250"
 DISULFID        254..263
                 /evidence="ECO:0000250"
 DISULFID        267..279
                 /evidence="ECO:0000250"
 DISULFID        285..310
                 /evidence="ECO:0000250"
 DISULFID        292..300
                 /evidence="ECO:0000250"
 DISULFID        314..327
                 /evidence="ECO:0000250"
 DISULFID        330..334
                 /evidence="ECO:0000250"
 DISULFID        338..359
                 /evidence="ECO:0000250"
 DISULFID        461..494
                 /evidence="ECO:0000250"
 DISULFID        550
                 /note="Interchain"
                 /evidence="ECO:0000250"
 DISULFID        675..900
                 /evidence="ECO:0000250"
 VAR_SEQ         746..757
                 /note="Missing (in isoform Short)"
                 /evidence="ECO:0000305"
                 /id="VSP_036680"
 HELIX           727..736
                 /evidence="ECO:0000244|PDB:4XST"
 SEQUENCE   1383 AA;  156757 MW;  4B919566902A944A CRC64;
 MGSGRGCETT AVPLLMAVAV AGGTAGHLYP GEVCPGMDIR NNLTRLHELE NCSVIEGHLQ
 ILLMFKTRPE DFRDLSFPKL IMITDYLLLF RVYGLESLKD LFPNLTVIRG SRLFFNYALV
 IFEMVHLKEL GLYNLMNITR GSVRIEKNNE LCYLATIDWS RILDYVEDNY IVLNKDDNEE
 CGDVCPGTAK GKTNCPATVI NGQFVERCWT HSHCQKVCPT ICKSHGCTAE GLCCHKECLG
 NCSEPDDPTK CVACRNFYLD GQCVETCPPP YYHFQDWRCV NFSFCQDLHY KCRNSRKPGC
 HQYVIHNNKC IPECPSGYTM NSSNLMCTPC LGPCPKVCQI LEGEKTIDSV TSAQELRGCT
 VINGSLIINI RGGNNLAAEL EANLGLIEEI SGFLKIRRSY ALVSLSFFRK LHLIRGETLE
 IGNYSFYALD NQNLRQLWDW NKHNLTITQG KLFFHYNPKL CLSEIHKMEE VSGTKGRQER
 NDIALKTNGD QASCENELLK FSFIRTSFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN
 VTEFDGQDAC GSNSWTVVDI DPPQRSNDPK SQTPSHPGWL MRGLKPWTQY AIFVKTLVTF
 SDERRTYGAK SDIIYVQTDA TNPSVPLDPI SVSNSSSQII LKWKPPSDPN GNITHYLVYW
 ERQAEDSELF ELDYCLKGLK LPSRTWSPPF ESDDSQKHNQ SEYDDSASEC CSCPKTDSQI
 LKELEESSFR KTFEDYLHNV VFVPRKTSSG NGAEDTRPSR KRRSLEEVGN VTATTPTLPD
 FPNISSTIAP TSHEEHRPFE KVVNKESLVI SGLRHFTGYR IELQACNQDS PEERSGVAAY
 VSARTMPEAK ADDIVGPVTH EIFENNVVHL MWQEPKEPNG LIVLYEVSYR RYGDEELHLC
 VSRKHFALER GCRLRGLSPG NYSVRVRATS LAGNGSWTEP TYFYVTDYLD VPSNIAKIII
 GPLIFVFLFS VVIGSIYLFL RKRQPDGPMG PLYASSNPEY LSASDVFPSS VYVPDEWEVP
 REKITLLREL GQGSFGMVYE GNAKDIIKGE VETRVAVKTV NESASLRERI EFLNEASVMK
 GFTCHHVVRL LGVVSKGQPT LVVMELMAHG DLKSHLRSLR PDAENNPGRP PPTLQEMIQM
 TAEIADGMAY LNAKKFVHRD LAARNCMVAH DFTVKIGDFG MTRDIYETDY YRKGGKGLLP
 VRWMSPESLK DGVFTASSDM WSFGVVLWEI TSLAEQPYQG LSNEQVLKFV MDGGYLDPPD
 NCPERLTDLM RMCWQFNPKM RPTFLEIVNL LKDDLHPSFP EVSFFYSEEN KAPESEELEM
 EFEDMENVPL DRSSHCQREE AGCREGGSSL SIKRTYDEHI PYTHMNGGKK NGRVLTLPRS
 NPS

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