UniProt Accession

 INSR_HUMAN; P06213; Q17RW0; Q59H98; Q9UCB7; Q9UCB8; Q9UCB9 

Genbank Protein ID

 M10051; X02160; M32972; M23100; M32823; M32824; M32825; M32826; M32827; M32828; M32829; M32830; M32831; M32832; M32833; M32834; M32835; M32836; M32837; M32838; M32839; M32840; M32841; M32842; AC010311; AC010526; AC010606; AC125387; BC117172; J03466; J05043; M76592; AB208861; M24555; M29929; M29930; M27197; M27195 

Genbank Nucleotide ID

 AAA59174.1; CAA26096.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAA59452.1; AAI17173.1; AAA59175.1; AAA59190.1; AAC37604.1; BAD92098.1; AAA59178.1; AAA59176.1; AAA59177.1; AAA86791.1; AAA86791.1 

Protein Name

 Insulin receptor 

Protein Synonyms/Alias

 IR; CD220; Insulin receptor subunit alpha; Insulin receptor subunit beta 

Gene Name

 INSR 

Gene Synonyms/Alias

  

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
1022	EWEVSREKITLLREL	ubiquitination	[1]
1047	GNARDIIKGEAETRV	ubiquitination	[1, 2]
1057	AETRVAVKTVNESAS	ubiquitination	[1, 2, 3, 4]
1112	LMAHGDLKSYLRSLR	acetylation	[5]
1352	GGSSLGFKRSYEEHI	ubiquitination	[2, 6]

Reference

 [1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [2] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [3] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [4] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [5] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [6] Global identification of modular cullin-RING ligase substrates.
 Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ.
 Cell. 2011 Oct 14;147(2):459-74. [PMID: 21963094] 

Functional Description

 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 phosphotyrosines 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). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. 

Sequence Annotation

 DOMAIN 622 695 Fibronectin type-III 1.
 DOMAIN 757 842 Fibronectin type-III 2.
 DOMAIN 850 946 Fibronectin type-III 3.
 DOMAIN 1023 1298 Protein kinase.
 NP_BIND 1104 1110 ATP.
 NP_BIND 1163 1164 ATP.
 REGION 733 741 Insulin-binding.
 REGION 999 999 Important for interaction with IRS1, SHC1
 REGION 1361 1364 PIK3R1-binding.
 ACT_SITE 1159 1159 Proton donor/acceptor.
 BINDING 1033 1033 ATP.
 BINDING 1057 1057 ATP.
 BINDING 1177 1177 ATP.
 MOD_RES 400 400 Phosphoserine.
 MOD_RES 401 401 Phosphotyrosine.
 MOD_RES 407 407 Phosphoserine.
 MOD_RES 992 992 Phosphotyrosine; by autocatalysis
 MOD_RES 999 999 Phosphotyrosine; by autocatalysis.
 MOD_RES 1011 1011 Phosphotyrosine; by autocatalysis
 MOD_RES 1185 1185 Phosphotyrosine; by autocatalysis.
 MOD_RES 1189 1189 Phosphotyrosine; by autocatalysis.
 MOD_RES 1190 1190 Phosphotyrosine; by autocatalysis.
 MOD_RES 1355 1355 Phosphotyrosine; by autocatalysis.
 MOD_RES 1361 1361 Phosphotyrosine; by autocatalysis.
 CARBOHYD 43 43 N-linked (GlcNAc...).
 CARBOHYD 52 52 N-linked (GlcNAc...).
 CARBOHYD 105 105 N-linked (GlcNAc...) (Potential).
 CARBOHYD 138 138 N-linked (GlcNAc...).
 CARBOHYD 242 242 N-linked (GlcNAc...).
 CARBOHYD 282 282 N-linked (GlcNAc...).
 CARBOHYD 322 322 N-linked (GlcNAc...) (Potential).
 CARBOHYD 364 364 N-linked (GlcNAc...).
 CARBOHYD 424 424 N-linked (GlcNAc...).
 CARBOHYD 445 445 N-linked (GlcNAc...).
 CARBOHYD 541 541 N-linked (GlcNAc...).
 CARBOHYD 633 633 N-linked (GlcNAc...) (Potential).
 CARBOHYD 651 651 N-linked (GlcNAc...) (Potential).
 CARBOHYD 698 698 N-linked (GlcNAc...) (Potential).
 CARBOHYD 769 769 N-linked (GlcNAc...).
 CARBOHYD 782 782 N-linked (GlcNAc...) (Potential).
 CARBOHYD 920 920 N-linked (GlcNAc...).
 CARBOHYD 933 933 N-linked (GlcNAc...) (Potential).
 DISULFID 35 53
 DISULFID 153 182
 DISULFID 186 209
 DISULFID 196 215
 DISULFID 219 228
 DISULFID 223 234
 DISULFID 235 243
 DISULFID 239 252
 DISULFID 255 264
 DISULFID 268 280
 DISULFID 286 311
 DISULFID 293 301
 DISULFID 315 328
 DISULFID 331 335
 DISULFID 339 360
 DISULFID 462 495
 DISULFID 551 551 Interchain.
 DISULFID 674 899
 DISULFID 825 834  

Keyword

 3D-structure; Alternative splicing; ATP-binding; Carbohydrate metabolism; Cell membrane; Cleavage on pair of basic residues; Complete proteome; Diabetes mellitus; Direct protein sequencing; Disease mutation; Disulfide bond; Glycoprotein; Kinase; Membrane; Nucleotide-binding; Phosphoprotein; Polymorphism; Receptor; Reference proteome; Repeat; Signal; Transferase; Transmembrane; Transmembrane helix; Tyrosine-protein kinase. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 1382 AA 

Protein Sequence

Gene Ontology

 GO:0005901; C:caveola; IDA:BHF-UCL.
 GO:0010008; C:endosome membrane; TAS:Reactome.
 GO:0005899; C:insulin receptor complex; IMP:BHF-UCL.
 GO:0005524; F:ATP binding; IDA:BHF-UCL.
 GO:0005525; F:GTP binding; IDA:BHF-UCL.
 GO:0043559; F:insulin binding; IDA:UniProtKB.
 GO:0005009; F:insulin-activated receptor activity; IDA:UniProtKB.
 GO:0005159; F:insulin-like growth factor receptor binding; IDA:BHF-UCL.
 GO:0004716; F:receptor signaling protein tyrosine kinase activity; IDA:BHF-UCL.
 GO:0000187; P:activation of MAPK activity; IMP:BHF-UCL.
 GO:0032148; P:activation of protein kinase B activity; IDA:BHF-UCL.
 GO:0005975; P:carbohydrate metabolic process; IEA:UniProtKB-KW.
 GO:0071363; P:cellular response to growth factor stimulus; IEA:Compara.
 GO:0031017; P:exocrine pancreas development; IEA:Compara.
 GO:0007186; P:G-protein coupled receptor signaling pathway; IDA:BHF-UCL.
 GO:0042593; P:glucose homeostasis; IMP:BHF-UCL.
 GO:0003007; P:heart morphogenesis; IMP:BHF-UCL.
 GO:0030238; P:male sex determination; IEA:Compara.
 GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:BHF-UCL.
 GO:0030335; P:positive regulation of cell migration; IMP:BHF-UCL.
 GO:0008284; P:positive regulation of cell proliferation; IDA:BHF-UCL.
 GO:0048639; P:positive regulation of developmental growth; IMP:BHF-UCL.
 GO:0045740; P:positive regulation of DNA replication; IMP:BHF-UCL.
 GO:0046326; P:positive regulation of glucose import; IDA:BHF-UCL.
 GO:0045725; P:positive regulation of glycogen biosynthetic process; IDA:BHF-UCL.
 GO:0045821; P:positive regulation of glycolysis; IMP:BHF-UCL.
 GO:0045840; P:positive regulation of mitosis; IMP:BHF-UCL.
 GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IMP:BHF-UCL.
 GO:0051897; P:positive regulation of protein kinase B signaling cascade; IMP:BHF-UCL.
 GO:0060267; P:positive regulation of respiratory burst; IDA:BHF-UCL.
 GO:0046777; P:protein autophosphorylation; IMP:UniProtKB.
 GO:0051290; P:protein heterotetramerization; IDA:UniProtKB.
 GO:0045995; P:regulation of embryonic development; IMP:BHF-UCL.
 GO:0006355; P:regulation of transcription, DNA-dependent; IMP:BHF-UCL.
 GO:0019087; P:transformation of host cell by virus; IMP:BHF-UCL. 

Interpro

 IPR000494; EGF_rcpt_L.
 IPR003961; Fibronectin_type3.
 IPR006211; Furin-like_Cys-rich_dom.
 IPR006212; Furin_repeat.
 IPR009030; Growth_fac_rcpt_N_dom.
 IPR013783; Ig-like_fold.
 IPR011009; Kinase-like_dom.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
 IPR008266; Tyr_kinase_AS.
 IPR020635; Tyr_kinase_cat_dom.
 IPR016246; Tyr_kinase_insulin-like_rcpt.
 IPR002011; Tyr_kinase_rcpt_2_CS. 

Pfam

 PF00041; fn3
 PF00757; Furin-like
 PF07714; Pkinase_Tyr
 PF01030; Recep_L_domain 

SMART

 SM00060; FN3
 SM00261; FU
 SM00219; TyrKc 

PROSITE

 PS50853; FN3
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00109; PROTEIN_KINASE_TYR
 PS00239; RECEPTOR_TYR_KIN_II 

PRINTS

 PR00109; TYRKINASE.