Editors' ChoiceRECEPTOR TURNOVER

Cdc42 Protects the EGF Receptor

Science's STKE  30 Sep 2003:
Vol. 2003, Issue 202, pp. tw383-TW383
DOI: 10.1126/stke.2003.202.tw383

It is thought that altered receptor turnover can account for increased expression of the cell surface receptor for epidermal growth factor (EGF) observed in some human cancers. Wu et al. have identified a signaling pathway that contributes to this phenotype. Activated EGF receptor stimulates activation of Cdc42, a small guanosine triphosphatase (GTPase) that controls cell growth, as well as cytoskeletal dynamics. Activated Cdc42 was shown to regulate the interaction of the EGF receptor with c-Cbl, an E3 ubiquitin ligase that catalyzes the ubiquitination and degradation of the receptor. Activated Cdc42 formed a complex with c-Cbl through an adaptor protein called Cool-1 (also known as β-Pix). Treatment of cells that overexpressed an activated form of Cdc42 with EGF promoted formation of the tricomplex and caused a decrease in EGF receptor ubiquitination. However, additional expression of a mutant form of Cool-1 that still binds to activated Cdc42, but not to c-Cbl, restored receptor ubiquitination. The authors propose that activated Cdc42 sequesters c-Cbl, thereby decreasing EGF receptor degradation. Cell transformation could result from sustained EGF receptor signaling. Cdc42 hydrolysis of GTP would release c-Cbl to interact with the receptor.

W. J. Wu, S. Tu, R. A. Cerione, Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation. Cell 114, 715-725 (2003). [Online Journal]