Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein

Abstract

Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the alpha subunit of the insulin receptor which activates the tyrosine kinase in the beta subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.

Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels

“…First, we examined IRS-1 tyrosine phosphorylation, regarded as a major proximal step in the activation of downstream insulin signalling [37]. In the absence of lipoproteins, the well-known stimulation of IRS-1 phosphorylation by insulin was seen.…”

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

“…The classical pathway involves activation of polypeptide growth factor receptors such as PDGF, which induces autophosphorylation of specific tyrosine residues, allowing these receptors to interact with the SH2 domain of the p85 regulatory adaptor subunit of PI3K, resulting in its localization to the membrane and activation of the kinase activity [135]. Other growth factor receptors act to phosphorylate an intermediate adaptor protein on tyrosine residues that binds p85 through its SH2 domain and induces an increase in PI3K specific activity; an example of this latter mechanism is the IGF-1 receptor, which phosphorylates IRS-1, an adaptor protein, which then recruits PI3K [136]. Direct interaction of PI3K following ligand binding with nonreceptor tyrosine kinases such as pp60 cSrc is also known to occur, with the SH3 domains of these srcfamily kinases interacting with two proline-rich regions on p85 to induce activation of the enzyme [137].…”

Lysophosphatidic acid-induced association of SHP-2 with SHPS-1: roles of RHO, FAK, and a SRC family kinase

“…SHP-2 binds directly to growth factor receptors, such as those of platelet-derived growth factor receptor and epidermal growth factor (EGF) receptor, and undergoes tyrosine phosphorylation in response to receptor stimulation by ligand Vogel et al, 1993;Matozaki and Kasuga, 1996;Neel and Tonks, 1997). Furthermore, in response to insulin, SHP-2 binds via its SH2 domains to IRS-1, a major substrate for the insulin receptor tyrosine kinase (Sun et al, 1991) and is thereby activated (Kuhne et al, 1993;Matozaki et al, 1995;Pluskey et al, 1995). The expression of a catalytically inactive SHP-2 inhibits insulin-induced activation of RAS and mitogen-activated protein (MAP) kinase (Noguchi et al, 1994;Milarski and Saltiel, 1994;Xiao et al, 1994;Yamauchi et al, 1995) as well as EGF-induced MAP kinase activation (Bennett et al, 1996) and thereby blocks DNA synthesis and cell proliferation.…”