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Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation.

Cdc42 is a Ras-related protein that has been implicated in the control of normal cell growth, and when improperly regulated, in cellular transformation and invasiveness. A variety of extracellular stimuli, including epidermal growth factor (EGF), activate Cdc42. Here, we show that activation of Cdc42 protects the EGF receptor from the negative regulatory activity of the c-Cbl ubiquitin ligase. Activated Cdc42 binds to p85Cool-1 (for cloned-out-of-library)/beta-Pix (for Pak-interactive exchange factor), a protein that directly associates with c-Cbl. This inhibits the binding of Cbl by the EGF receptor and thus prevents Cbl from catalyzing receptor ubiquitination. The role played by Cdc42 in regulating the timing of EGF receptor-Cbl interactions is underscored by the fact that constitutively active Cdc42(F28L), by persistently blocking the binding of Cbl to these receptors, leads to their aberrant accumulation and sustained EGF-stimulated ERK activation, thus resulting in cellular transformation.

Pubmed ID: 14505571


  • Wu WJ
  • Tu S
  • Cerione RA



Publication Data

September 19, 2003

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM40654
  • Agency: NIGMS NIH HHS, Id: GM47458

Mesh Terms

  • 3T3 Cells
  • Animals
  • Cell Cycle Proteins
  • Cell Division
  • Cell Membrane
  • Cell Transformation, Neoplastic
  • Epidermal Growth Factor
  • Feedback, Physiological
  • Guanine Nucleotide Exchange Factors
  • Mice
  • Mitogen-Activated Protein Kinases
  • Protein Binding
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-cbl
  • Receptor, Epidermal Growth Factor
  • Rho Guanine Nucleotide Exchange Factors
  • Ubiquitin-Protein Ligases
  • cdc42 GTP-Binding Protein