Nature Cell Biology
- 8, 945 - 956 (2006)
Published online: 6 August 2006; | doi:10.1038/ncb1453
Cool-1 functions as an essential regulatory node for EGFreceptor- and Src-mediated cell growthQiyu Feng1, 3, Dan Baird2, 3, Xu Peng1, Jianbin Wang1, Thi Ly1, Jun-Lin Guan1 & Richard A. Cerione1, 21
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA. 2
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA. 3
These authors contributed equally to this work.
Correspondence should be addressed to Richard A. Cerione rac1@cornell.edu Cool-1 (cloned-out of library 1) has a key role in regulating epidermal growth factor receptor (EGFR) degradation. Here, we show that Cool-1 performs this function by functioning as both an upstream activator and downstream target for Cdc42. EGF-dependent phosphorylation of Cool–1 enables it to act as a nucleotide exchange factor for Cdc42 and to form a complex with the E3 ligase Cbl, thus regulating Cbl-catalysed EGFR degradation. The EGF-dependent phosphorylation is normally transient; however, Cool-1 phosphorylation is sustained in cells expressing v–Src and is essential for cellular transformation, as well as for v-Src-induced tumour formation in mice. These findings demonstrate that the regulated phosphorylation of Cool-1 is necessary to maintain the balance between normal signalling by EGFR and Src versus aberrant growth and transformation.
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