InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: INSR

Summary

InnateDB Protein

IDBP-22533.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

INSR

Protein Name

insulin receptor

Synonyms

CD220; HHF5;

Species

Homo sapiens

Ensembl Protein

ENSP00000303830

InnateDB Gene

IDBG-22529 (INSR)

Protein Structure

UniProt Annotation

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 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. {ECO:0000269PubMed:12138094, ECO:0000269PubMed:16314505, ECO:0000269PubMed:16831875, ECO:0000269PubMed:8257688, ECO:0000269PubMed:8276809, ECO:0000269PubMed:8452530, ECO:0000269PubMed:9428692}.

Subcellular Localization

Cell membrane; Single-pass type I membrane protein.

Disease Associations

Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive. {ECO:0000269PubMed:10443650, ECO:0000269PubMed:12023989, ECO:0000269PubMed:17201797, ECO:0000269PubMed:2365819, ECO:0000269PubMed:8314008}. Note=The disease is caused by mutations affecting the gene represented in this entry.Leprechaunism (LEPRCH) [MIM:246200]: Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive. {ECO:0000269PubMed:12538626, ECO:0000269PubMed:12970295, ECO:0000269PubMed:1607067, ECO:0000269PubMed:1730625, ECO:0000269PubMed:2365819, ECO:0000269PubMed:2479553, ECO:0000269PubMed:2834824, ECO:0000269PubMed:7538143, ECO:0000269PubMed:7815442, ECO:0000269PubMed:8188715, ECO:0000269PubMed:8326490, ECO:0000269PubMed:8419945, ECO:0000269PubMed:8636294, ECO:0000269PubMed:9249867, ECO:0000269PubMed:9703342}. Note=The disease is caused by mutations affecting the gene represented in this entry.Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269PubMed:1470163, ECO:0000269PubMed:1607076, ECO:0000269PubMed:7657032}. Note=The gene represented in this entry may be involved in disease pathogenesis.Familial hyperinsulinemic hypoglycemia 5 (HHF5) [MIM:609968]: Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. {ECO:0000269PubMed:15161766}. Note=The disease is caused by mutations affecting the gene represented in this entry.Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]: Characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. {ECO:0000269PubMed:10733238, ECO:0000269PubMed:11260230, ECO:0000269PubMed:12107746, ECO:0000269PubMed:12970295, ECO:0000269PubMed:1563582, ECO:0000269PubMed:1963473, ECO:0000269PubMed:2002058, ECO:0000269PubMed:2168397, ECO:0000269PubMed:2365819, ECO:0000269PubMed:2544998, ECO:0000269PubMed:3283938, ECO:0000269PubMed:8243830, ECO:0000269PubMed:8288049, ECO:0000269PubMed:8314008, ECO:0000269PubMed:8388389, ECO:0000269PubMed:9175790}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas. {ECO:0000269PubMed:10207053, ECO:0000269PubMed:2369896, ECO:0000269PubMed:9202395, ECO:0000269PubMed:9355755}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 135 experimentally validated interaction(s) in this database.
They are also associated with 12 interaction(s) predicted by orthology.

Experimentally validated
Total	135 [view]
Protein-Protein	132 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	12 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004714	transmembrane receptor protein tyrosine kinase activity
GO:0004716	receptor signaling protein tyrosine kinase activity
GO:0005009	insulin-activated receptor activity
GO:0005159	insulin-like growth factor receptor binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0005525	GTP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0031994	insulin-like growth factor I binding
GO:0031995	insulin-like growth factor II binding
GO:0043548	phosphatidylinositol 3-kinase binding
GO:0043559	insulin binding
GO:0043560	insulin receptor substrate binding
GO:0051425	PTB domain binding

Biological Process

GO:0000187	activation of MAPK activity
GO:0001934	positive regulation of protein phosphorylation
GO:0003007	heart morphogenesis
GO:0005975	carbohydrate metabolic process
GO:0006355	regulation of transcription, DNA-templated
GO:0006468	protein phosphorylation
GO:0007169	transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007186	G-protein coupled receptor signaling pathway
GO:0008284	positive regulation of cell proliferation
GO:0008286	insulin receptor signaling pathway
GO:0008544	epidermis development
GO:0009887	organ morphogenesis
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0019087	transformation of host cell by virus
GO:0023014	signal transduction by phosphorylation
GO:0030238	male sex determination
GO:0030335	positive regulation of cell migration
GO:0031017	exocrine pancreas development
GO:0032147	activation of protein kinase activity
GO:0032148	activation of protein kinase B activity
GO:0032869	cellular response to insulin stimulus
GO:0038083	peptidyl-tyrosine autophosphorylation
GO:0042593	glucose homeostasis
GO:0043410	positive regulation of MAPK cascade
GO:0045429	positive regulation of nitric oxide biosynthetic process
GO:0045725	positive regulation of glycogen biosynthetic process
GO:0045740	positive regulation of DNA replication
GO:0045821	positive regulation of glycolytic process
GO:0045840	positive regulation of mitosis
GO:0045995	regulation of embryonic development
GO:0046326	positive regulation of glucose import
GO:0046777	protein autophosphorylation
GO:0048639	positive regulation of developmental growth
GO:0051290	protein heterotetramerization
GO:0051897	positive regulation of protein kinase B signaling
GO:0060267	positive regulation of respiratory burst
GO:0071363	cellular response to growth factor stimulus

Cellular Component

GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0005899	insulin receptor complex
GO:0005901	caveola
GO:0010008	endosome membrane
GO:0016020	membrane
GO:0016021	integral component of membrane
GO:0043235	receptor complex
GO:0070062	extracellular vesicular exosome

Protein Structure and Domains

PDB ID

InterPro

IPR000494 EGF receptor, L domain
IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR003961 Fibronectin, type III
IPR006211 Furin-like cysteine-rich domain
IPR006212 Furin-like repeat
IPR009030 Insulin-like growth factor binding protein, N-terminal
IPR011009 Protein kinase-like domain
IPR016246 Tyrosine-protein kinase, insulin-like receptor
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF01030
PF00069
PF07714
PF00041
PF01108
PF00757

PRINTS

PR00109

PIRSF

PIRSF000620

SMART

SM00220
SM00060
SM00261
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References