INSR - Insulin receptor - human protein (Function)
 
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INSR »  Insulin receptor   [ EC 2.7.10.1 ]  (IR)
 
Protein also known as:  CD antigen CD220. Cleaved into:  Insulin receptor subunit alpha; Insulin receptor subunit beta.
Gene name:  INSR
Entry whose protein(s) existence is based on evidence at protein level
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1 365 2
GENE REF ISO

Function

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Overview 
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).  
8
  • CuratedUniProtKB
Isoform  Short   Has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed12138094 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, PubMed16831875 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.  
8
  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
1
  • IDABHF-UCL
GTP bindingdefinition[GO:0005525]  
1
  • IDABHF-UCL
Insulin bindingdefinition[GO:0043559]  
2
  • IPIBHF-UCL
  • IDAUniProtKB
Insulin receptor substrate bindingdefinition[GO:0043560]  
3
  • IPIBHF-UCL
  • IPIUniProtKB
Insulin-activated receptor activitydefinition[GO:0005009]  
2
  • IDAUniProtKB
  • IDABHF-UCL
Insulin-like growth factor I bindingdefinition[GO:0031994]  
1
  • IPIBHF-UCL
Insulin-like growth factor II bindingdefinition[GO:0031995]  
1
  • IPIBHF-UCL
Insulin-like growth factor receptor bindingdefinition[GO:0005159]  
1
  • IDABHF-UCL
Phosphatidylinositol 3-kinase bindingdefinition[GO:0043548]  
2
  • IPIUniProtKB
Protein bindingdefinition[GO:0005515]  
36
  • IPIIntAct
  • IPIHGNC
  • IPIUniProtKB
Protein tyrosine kinase activitydefinition[GO:0004713]  
2
  • IMPUniProtKB
  • IDABHF-UCL
PTB domain bindingdefinition[GO:0051425]  
1
  • IPIUniProtKB
Receptor signaling protein tyrosine kinase activitydefinition[GO:0004716]  
1
  • IDABHF-UCL
SH2 domain bindingdefinition[GO:0042169]  
1
  • IPIUniProtKB
GO biological process 
Activation of MAPK activitydefinition[GO:0000187]  
1
  • IMPBHF-UCL
Activation of protein kinase activitydefinition[GO:0032147]  
1
  • IMPBHF-UCL
Activation of protein kinase B activitydefinition[GO:0032148]  
1
  • IDABHF-UCL
Carbohydrate metabolic processdefinition[GO:0005975]  
  • IEAUniProtKB KW
Cellular response to growth factor stimulusdefinition[GO:0071363] silver  
  • IEAOrtholog Compara
Cellular response to insulin stimulusdefinition[GO:0032869]  
1
  • IDABHF-UCL
Exocrine pancreas developmentdefinition[GO:0031017] silver  
  • IEAOrtholog Compara
G-protein coupled receptor signaling pathwaydefinition[GO:0007186]  
1
  • IDABHF-UCL
Glucose homeostasisdefinition[GO:0042593]  
1
  • IMPBHF-UCL
Heart morphogenesisdefinition[GO:0003007]  
1
  • IMPBHF-UCL
Insulin receptor signaling pathwaydefinition[GO:0008286]  
2
  • IDAUniProtKB
  • IDABHF-UCL
Male sex determinationdefinition[GO:0030238] silver  
  • IEAOrtholog Compara
Peptidyl-tyrosine phosphorylationdefinition[GO:0018108]  
1
  • IDABHF-UCL
Positive regulation of cell migrationdefinition[GO:0030335]  
1
  • IMPBHF-UCL
Positive regulation of cell proliferationdefinition[GO:0008284]  
2
  • IDABHF-UCL
Positive regulation of developmental growthdefinition[GO:0048639]  
1
  • IMPBHF-UCL
Positive regulation of DNA replicationdefinition[GO:0045740]  
1
  • IMPBHF-UCL
Positive regulation of glucose importdefinition[GO:0046326]  
2
  • NASBHF-UCL
Positive regulation of glycogen biosynthetic processdefinition[GO:0045725]  
1
  • IDABHF-UCL
Positive regulation of glycolytic processdefinition[GO:0045821]  
1
  • IMPBHF-UCL
Positive regulation of MAPK cascadedefinition[GO:0043410]  
1
  • IMPBHF-UCL
Positive regulation of mitosisdefinition[GO:0045840]  
1
  • IMPBHF-UCL
Positive regulation of nitric oxide biosynthetic processdefinition[GO:0045429]  
1
  • IMPBHF-UCL
Positive regulation of protein kinase B signalingdefinition[GO:0051897]  
1
  • IMPBHF-UCL
Positive regulation of protein phosphorylationdefinition[GO:0001934]  
1
  • IDABHF-UCL
Positive regulation of respiratory burstdefinition[GO:0060267]  
1
  • IDABHF-UCL
Protein autophosphorylationdefinition[GO:0046777]  
3
  • IMPUniProtKB
  • IDABHF-UCL
Protein heterotetramerizationdefinition[GO:0051290]  
1
  • IDAUniProtKB
Regulation of embryonic developmentdefinition[GO:0045995]  
1
  • IMPBHF-UCL
Regulation of transcription, DNA-templateddefinition[GO:0006355]  
1
  • IMPBHF-UCL
Signal transduction by phosphorylationdefinition[GO:0023014]  
1
  • IDAGOC
Transformation of host cell by virusdefinition[GO:0019087]  
1
  • IMPBHF-UCL
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.10.1: ATP + a [protein]-L-tyrosine ADP + a [protein]-L-tyrosine phosphate.  
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  • CuratedUniProtKB
It is regulated in the following manner
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.  
5
  • CuratedUniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Adherens junction  hsa04520+3643  
Aldosterone-regulated sodium reabsorption  hsa04960+3643  
Insulin signaling pathway  hsa04910+3643  
Type II diabetes mellitus  hsa04930+3643  
According to Reactome, this protein belongs to the following pathway:
Signal Transduction  REACT_111102  
 

Keywords

Biological process 
Carbohydrate metabolism  definition   [KW-0119]
Molecular function 
Kinase  definition   [KW-0418]
Receptor  definition   [KW-0675]
Transferase  definition   [KW-0808]
Tyrosine-protein kinase  definition   [KW-0829]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Enzyme and pathway databases
SABIO-RK: P06213
Other
GeneWiki: Insulin_receptor
GenomeRNAi: 3643
PRO: PR:P06213
Chemistry
GuidetoPHARMACOLOGY: 1800