Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation

Abstract

The proteins Grb2-Sem-5, Shc and Sos have been implicated in the signalling pathway from tyrosine kinase receptors to Ras. Grb2-Sem-5 binds directly to murine Sos1, a Ras exchange factor, through two SH3 domains. Sos is also associated with ligand-activated tyrosine kinase receptors which bind Grb2-Sem-5, and with the Grb2-Sem-5 binding protein, Shc. Ectopic expression of Drosophila Sos stimulates morphological transformation of rodent fibroblasts. These data define a pathway by which tyrosine kinases act through Ras to control cell growth and differentiation.

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.…”

Fibroblast growth factor receptor-1 mediates chemotaxis independently of direct SH2-domain protein binding

“…Activation of di erent signal transduction molecules is believed to initiate distinct signaling chains, each giving rise to unique responses. For example, binding of Grb2 to the activated epidermal growth factor receptor or plateletderived growth factor (PDGF) receptor initiates the Ras-dependent MAP kinase pathway which is believed to be the major pathway for mitogenicity Egan et al, 1993) whereas activation of PI 3-kinase is involved in chemotactic signaling by the PDGF b-receptor .…”

The G12 coupled thrombin receptor stimulates mitogenesis through the Shc SH2 domain

“…Shc contains an N-terminal phosphotyrosine binding motif (PTB), a central collagen homology domain (CH) where the primary site of tyrosine phosphorylation (Y317) resides, and a C-terminal SH2 domain (Kavanaugh and Williams, 1994;Pelicci et al, 1992). After autophosphorylation of receptors, Shc is recruited to the receptor via phosphotyrosine binding motifs (Rozakis-Adcock et al, 1992;Egan et al, 1993). The recent ®nding that the epidermal growth factor receptor (EGFR) requires the Shc SH2, while the insulin receptor (InsR) requires the Shc PTB to couple to mitogenesis (Ricketts et al, 1996) demonstrates that these domains may serve di erent functions.…”