Phospho-IRS1 (Ser612)

This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]

Full Name

Insulin Receptor Substrate 1

Function

May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity).

Biological Process

Cellular response to fatty acidISS:ARUK-UCL
Cellular response to insulin stimulusManual Assertion Based On ExperimentIMP:BHF-UCL
Glucose homeostasisManual Assertion Based On ExperimentTAS:BHF-UCL
Insulin receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Insulin-like growth factor receptor signaling pathwayManual Assertion Based On ExperimentIPI:UniProtKB
Negative regulation of insulin receptor signaling pathwayISS:BHF-UCL
Negative regulation of insulin secretionManual Assertion Based On ExperimentIDA:BHF-UCL
Phosphatidylinositol 3-kinase signalingManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of cell population proliferation1 PublicationNAS:BHF-UCL
Positive regulation of fatty acid beta-oxidationManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of glucose importManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of glucose metabolic processManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of glycogen biosynthetic processManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of insulin receptor signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of phosphatidylinositol 3-kinase activityISS:BHF-UCL
Response to insulinManual Assertion Based On ExperimentIDA:BHF-UCL
Response to peptide hormoneISS:BHF-UCL
Signal transductionManual Assertion Based On ExperimentTAS:ProtInc

Cellular Location

Caveola; Cytoplasm; Cytosol; Insulin receptor complex; Intracellular membrane-bounded organelle; Nucleoplasm; Nucleus; Plasma membrane

Involvement in disease

Diabetes mellitus, non-insulin-dependent (NIDDM):
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.

PTM

Serine phosphorylation of IRS1 is a mechanism for insulin resistance. Ser-312 phosphorylation inhibits insulin action through disruption of IRS1 interaction with the insulin receptor (By similarity).
Phosphorylation of Tyr-896 is required for GRB2-binding (By similarity).
Phosphorylated by ALK. Phosphorylated at Ser-270, Ser-307, Ser-636 and Ser-1101 by RPS6KB1; phosphorylation induces accelerated degradation of IRS1 (PubMed:18952604).
Phosphorylated on tyrosine residues in response to insulin (PubMed:23401856).
In skeletal muscles, dephosphorylated on Tyr-612 by TNS2 under anabolic conditions; dephosphorylation results in the proteasomal degradation of IRS1 (PubMed:23401856).
Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent manner, leading to its degradation: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2).