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Cell. 2003 Sep 19;114(6):715-25.

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

Author information

1
Department of Molecular Medicine, Veterinary Medical Center, Baker Laboratory, Cornell University, Ithaca, NY 14853, USA.

Abstract

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.

PMID:
14505571
DOI:
10.1016/s0092-8674(03)00688-3
[Indexed for MEDLINE]
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