Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Cycle Proteins / physiology*
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Cell Proliferation*
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Cell Transformation, Neoplastic*
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Endocytosis
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ErbB Receptors / physiology*
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism
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Guanine Nucleotide Exchange Factors / physiology*
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Male
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Mice
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Mice, Nude
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NIH 3T3 Cells
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Neoplasm Transplantation
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Neoplasms, Experimental / pathology
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Oncogene Protein pp60(v-src) / biosynthesis
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Oncogene Protein pp60(v-src) / physiology*
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Phosphorylation
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Phosphotyrosine / metabolism
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Protein Binding
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Proto-Oncogene Proteins c-cbl / metabolism
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RNA Interference
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Rho Guanine Nucleotide Exchange Factors
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Signal Transduction
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Transplantation, Heterologous
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cdc42 GTP-Binding Protein / physiology*
Substances
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Cell Cycle Proteins
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Guanine Nucleotide Exchange Factors
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Rho Guanine Nucleotide Exchange Factors
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Phosphotyrosine
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Proto-Oncogene Proteins c-cbl
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ErbB Receptors
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Oncogene Protein pp60(v-src)
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cdc42 GTP-Binding Protein
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Cbl protein, mouse