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.
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, Ubiquitin-Protein Ligases, cdc42 GTP-Binding Protein
Cell
Date: Sep. 19, 2003
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