Cool-1 functions as an essential regulatory node for EGF receptor- and Src-mediated cell growth

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...

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Bibliographic Details
Published inNature cell biology Vol. 8; no. 9; pp. 945 - 956
Main Authors Feng, Qiyu, Baird, Dan, Peng, Xu, Wang, Jianbin, Ly, Thi, Guan, Jun-Lin, Cerione, Richard A
Format Journal Article
LanguageEnglish
Published England 01.09.2006
Subjects
Animals
cdc42 GTP-Binding Protein - physiology
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Cycle Proteins - physiology
Cell Proliferation
Cell Transformation, Neoplastic
Endocytosis
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - metabolism
Guanine Nucleotide Exchange Factors - physiology
Male
Mice
Mice, Nude
Neoplasm Transplantation
Neoplasms, Experimental - pathology
NIH 3T3 Cells
Oncogene Protein pp60(v-src) - biosynthesis
Oncogene Protein pp60(v-src) - physiology
Phosphorylation
Phosphotyrosine - metabolism
Protein Binding
Proto-Oncogene Proteins c-cbl - metabolism
Receptor, Epidermal Growth Factor - physiology
Rho Guanine Nucleotide Exchange Factors
RNA Interference
Signal Transduction
Transplantation, Heterologous
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Summary: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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ISSN:1465-7392
DOI:10.1038/ncb1453