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

Nature. 1992 Dec 17;360(6405):689-92. doi: 10.1038/360689a0.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Caenorhabditis elegans / genetics
  • Cell Line, Transformed
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • GRB2 Adaptor Protein
  • GTP-Binding Proteins / metabolism*
  • Genes, ras
  • Genes, src
  • Neurites / physiology
  • Neurites / ultrastructure
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Oncogenes*
  • PC12 Cells
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / genetics
  • Proteins / metabolism*
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • Oncogene Proteins
  • Proteins
  • Epidermal Growth Factor
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • GTP-Binding Proteins