Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling

Abstract

Many of the actions of receptor tyrosine kinases are mediated by the protein Ras, including the activation of various downstream serine/threonine kinases and the stimulation of growth and differentiation. The human protein Grb2 binds to ligand-activated growth factor receptors and downstream effector proteins through its Src-homology (SH) domains SH2 and SH3, respectively, and like its homologue from Caenorhabditis elegans, Sem-5, apparently forms part of a highly conserved pathway by which these receptors can control Ras activity. Here we show that the SH3 domains of Grb2 bind to the carboxy-terminal part of hSos1, the human homologue of the Drosophila guanine-nucleotide-releasing factor for Ras, which is essential for control of Ras activity by epidermal growth factor receptor and sevenless. Moreover, a synthetic 10-amino-acid peptide containing the sequence PPVPPR specifically blocks the interaction. These results indicate that the Grb2/hSos1 complex couples activated EGF receptor to Ras signalling.

Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2

“…The full-length GST-Grb2, but not GST itself, bound Dab2 from a BAC1.2F5 cell lysate . While the SH2 domain failed to bind Sos, both the C-and N-terminal SH3 domains of Grb2 bound mSos1, with the N-terminal SH3 domain being more e ective than the C-terminal domain, similar to results published previously (Egan et al, 1993;Rozakis-Adcock et al, 1993;Li et al, 1993;Buday and Downward, 1993). The constructs of the Grb2 fusion protein and results of this experiment are illustrated in Figure 6b.…”

New insights into protein‐tyrosine kinase receptor signaling complexes

“…regions of sequence in their carboxy-termini to the SH3 domains of Grb-2 (Buday & Downward, 1993;Egan et al, 1993;Gale et al, 1993;Li et al, 1993;Olivier et al, 1993;Rozakis-Adcock et al, 1993;Simon et al, 1993). This is the first clear description of a physiological ligand for an SH3 domain.…”

Signal transduction in mammary tumorigenesis: a transgenic perspective

“…Grb2 contains a single SH2 domain anked by two SH3 domains, the later domain constitutively associates with Sos (Buday and Downward, 1993;Chardin et al, 1993;Egan et al, 1993;Gale et al, 1993;Li et al, 1993;Rozakis-Adcock et al, 1993). Shc proteins are thought to promote Ras activation by indirectly recruiting Grb2 Rozakis-Adcock et al, 1992) through tyrosine phosphorylation of sites conforming to consensus Grb2 SH2 binding sites (Gotoh et al, 1997;Salcini et al, 1994;Songyang et al, 1994).…”