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 RIS Download

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