Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases

Abstract

The mammalian shc gene encodes two overlapping, widely expressed proteins of 46 and 52K, with a carboxy-terminal SH2 domain that binds activated growth factor receptors, and a more amino-terminal glycine/proline-rich region. These shc gene products (Shc) are transforming when overexpressed in fibroblasts. Shc proteins become phosphorylated on tyrosine in cells stimulated with a variety of growth factors, and in cells transformed by v-src (ref. 2), suggesting that they are tyrosine kinase targets that control a mitogenic signalling pathway. Here we report that tyrosine-phosphorylated Shc proteins form a specific complex with a non-phosphorylated 23K polypeptide encoded by the grb2/sem-5 gene. The grb2/sem-5 gene product itself contains an SH2 domain, which mediates binding to Shc, and is implicated in activation of the Ras guanine nucleotide-binding protein by tyrosine kinases in both Caenorhabditis elegans and mammalian cells. Consistent with a role in signalling through Ras, shc overexpression induced Ras-dependent neurite outgrowth in PC12 cells. These results suggest that Shc tyrosine phosphorylation can couple tyrosine kinases to Grb2/Sem-5, through formation of a Shc-Grb2/Sem-5 complex, and thereby regulate the mammalian Ras signalling pathway.

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). Ras activity is required for e cient ErbB-2 (Ben- Levy et al, 1994;Dankort et al, 1997) and PyV-MT-(Jelinek and Hassell, 1992) mediated signaling.…”

New insights into protein‐tyrosine kinase receptor signaling complexes

“…Grb-2 has been shown to form complexes with tyrosine-phosphorylated forms of the Shc protein, another SH2 domain-containing family member Rozakis-Adcock et al, 1992;Egan et al, 1993;Skolnik et al, 1993). The Shc proteins have a carboxy-terminal SH2 domain and an amino-terminal glycine/proline-rich region and have been shown to be transforming when overexpressed in fibroblasts .…”

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

“…The adaptor protein Shc is an early mediator of this process (Rozakis-Adcock et al, 1992). 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).…”

“…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.…”

“…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. Shc binding to the receptor is followed by its phosphorylation on Y317, which forms a GRB2 binding site (Salcini et al, 1994) and results in recruitment of cytosolic GRB2/SOS complexes to the cell membrane (Rozakis-Adcock et al, 1992, 1993Chardin et al, 1993). Once localized to the membrane, SOS-catalyzes the exchange of GDP for GTP on Ras (McCormick, 1993;Aronheim et al, 1994).…”