Cbl-b, a Member of the Sli-1/c-Cbl Protein Family, Inhibits Vav-mediated c-Jun N-terminal Kinase Activation

Oncogene. 1997 Nov 20;15(21):2511-20. doi: 10.1038/sj.onc.1201430.

Abstract

We have used the yeast two-hybrid system to identify proteins that interact with Vav, a GDP/GTP exchange factor for the Rac-1 GTPase that plays an important role in cell signaling and oncogenic transformation. This experimental approach resulted in the isolation of Cbl-b, a signal transduction molecule highly related to the mammalian c-cbl proto-oncogene product and to the C. elegans Sli-1 protein, a negative regulator of the EGF-receptor-like Let23 protein. The interaction between Vav and Cbl-b requires the entire SH3-SH2-SH3 carboxy-terminal domain of Vav and a long stretch of proline-rich sequences present in the central region of Cbl-b. Stimulation of quiescent rodent fibroblasts with either epidermal or platelet-derived growth factors induces an increased affinity of Vav for Cbl-b and results in the subsequent formation of a Vav-dependent trimeric complex with the ligand-stimulated tyrosine kinase receptors. During this process, Vav, but not Cbl-b, becomes highly phosphorylated on tyrosine residues. Overexpression of Cbl-b inhibits the signal transduction pathway of Vav that leads to the stimulation of c-Jun N-terminal kinase. By contrast, expression of truncated Cbl-b proteins and of missense mutants analogous to those found in inactive Sli-1 proteins have no detectable effect on Vav activity. These results indicate that Vav and Cbl-b act coordinately in the first steps of tyrosine protein kinase receptor-mediated signaling and suggest that members of the Sli-1/Cbl family are also negative regulators of signal transduction in mammalian cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Cycle Proteins*
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases*
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Proto-Oncogene Proteins c-vav
  • Rabbits
  • Receptor Protein-Tyrosine Kinases / physiology
  • Signal Transduction
  • Ubiquitin-Protein Ligases*
  • rac GTP-Binding Proteins
  • src Homology Domains

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins c-vav
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Protein Kinases
  • Receptor Protein-Tyrosine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • GTP-Binding Proteins
  • rac GTP-Binding Proteins