Feng Q, Baird D, Peng X, Wang J, Ly T, Guan JL, Cerione RA

Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.

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.

Mesh Terms:
Animals, Cell Cycle Proteins, Cell Proliferation, Cell Transformation, Neoplastic, Endocytosis, Guanine Nucleotide Exchange Factors, Male, Mice, Mice, Nude, NIH 3T3 Cells, Neoplasm Transplantation, Neoplasms, Experimental, Oncogene Protein pp60(v-src), Phosphorylation, Phosphotyrosine, Protein Binding, Proto-Oncogene Proteins c-cbl, RNA Interference, Receptor, Epidermal Growth Factor, Signal Transduction, Transplantation, Heterologous, cdc42 GTP-Binding Protein

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