Binding of the Ras Activator Son of Sevenless to Insulin Receptor Substrate-1 Signaling Complexes

Abstract

Signal transmission by insulin involves tyrosine phosphorylation of a major insulin receptor substrate (IRS-1) and exchange of Ras-bound guanosine diphosphate for guanosine triphosphate. Proteins containing Src homology 2 and 3 (SH2 and SH3) domains, such as the p85 regulatory subunit of phosphatidylinositol-3 kinase and growth factor receptor-bound protein 2 (GRB2), bind tyrosine phosphate sites on IRS-1 through their SH2 regions. Such complexes in COS cells were found to contain the heterologously expressed putative guanine nucleotide exchange factor encoded by the Drosophila son of sevenless gene (dSos). Thus, GRB2, p85, or other proteins with SH2-SH3 adapter sequences may link Sos proteins to IRS-1 signaling complexes as part of the mechanism by which insulin activates Ras.

Insulin-like growth factor-I signaling in human neuroblastoma cells

“…p66 and p52 Shc are strongly phosphorylated in N cells by IGF-I, but are very weakly phosphorylated in one S cell line, SK-N-AS. Whereas Akt is exclusively activated by the PI 3-K pathway and is dependent on IRS protein activation (Franke et al, 1997), MAPK activation through Grb2/SOS-Ras can occur by either IRS or Shc signaling (Baltensperger et al, 1993;Sasaoka et al, 1994). We have previously suggested that Shc, rather than IRS-2, plays a major role in the activation of MAPK in SH-SY5Y cells (Kim et al, 1998a).…”

Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma

“…13,14 For example, the 897 YVNI motif of IRS-1 binds to the growth factor receptor-bound protein 2 (Grb2) adapter molecule, the 1180 YIDL motif binds to Syp protein tyrosine phosphatase, and 613 YMPM and 942 YMKM motifs bind to the p85 subunit of phosphatidylinositol-3 kinase (PI3K). 13,[15][16][17][18][19] The Grb2 binds to PY-IRS-1 19,20 leading to sequential activation of p21 ras , mitogen-activated protein kinase kinase (MAPKK), and MAP kinase (MAPK) [20][21][22][23] (see Fig. 1).…”

A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies.

“…These phosphorylation sites then serve as docking sites for several proteins possessing SH2 domains. Thus, phosphorylated IRS-1 binds to and stimulates phosphatidylinositol (PI) 3-kinase, SHPTP-2, and via GRb2-SOS the Ras and mitogen-activated protein (MAP) kinase pathways (11)(12)(13)(14)(15)(16)(17)(18). Although Gly 972 is not directly located in a phosphorylation site, it is conserved in human, rat, and murine IRS-1 and lies between two potential sites of tyrosine phosphorylation involved in binding the p85 subunit of PI 3-kinase.…”