Insulin receptor substrate 1

Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the IRS1 gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies. Insulin receptor substrate 1 plays a key role in transmitting signals from the insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1) to intracellular pathways PI3K / Akt and Erk MAP kinase pathways. Tyrosine phosphorylation of IRS-1 by insulin receptor (IR) introduces multiple binding sites for proteins bearing SH2 homology domain, such as PI3K, Grb-2/Sos complex and SHP2. PI3K, involved in interaction with IRS-1, produces PIP3, which, in turn, recruits Akt kinase. Further, Akt kinase is activated via phosphorylation of its T308 residue and analogous sites in PKC by PDK1. This phosphorylation is absent in tissues lacking IRS-1. The cascade is followed by glucose uptake. Formation of the Grb-2/Sos complex, also known as the RAS guanine nucleotide exchange factor complex, results in ERK1/2 activation. IRS-1 signal transduction may be inhibited by SHP2 in some tissues. Tyrosine phosphorylation of the insulin receptors or IGF-1 receptors, upon extracellular ligand binding, induces the cytoplasmic binding of IRS-1 to these receptors, through its PTB domains. Multiple tyrosine residues of IRS-1 itself are then phosphorylated by these receptors. This enables IRS-1 to activate several signalling pathways, including the PI3K pathway and the MAP kinase pathway. An alternative multi-site phosphorylation of Serine/Threonine in IRS-1 regulates insulin signaling positively and negatively.