Tyrosine phosphorylation and translocation of the c-cbl protein after activation of tyrosine kinase signaling pathways.
The c-cbl protooncogene product (c-Cbl) is a 120-kDa protein that has been shown to bind to the Src homology 3 domains of various proteins, suggesting its involvement in signal transduction pathways. We identified one of the most prominent tyrosine-phosphorylated proteins in Fc gamma receptor (Fc gamma R)-stimulated macrophages to be c-Cbl. Tyrosine phosphorylation of c-Cbl occurred within 20 s after stimulation and reached maximum levels within 3-5 min. c-Cbl was also tyrosine- phosphorylated in epidermal growth factor (EGF) receptor-overexpressing cells upon EGF stimulation, in macrophages in response to CSF-1 treatment, and in v-src transformed cells. Furthermore, we found that c-Cbl associated with these kinases in vivo. In vitro, c-Cbl bound to the Src homology 3 domains of Src, Fyn, and Lyn in both unstimulated and Fc gamma R-stimulated macrophages. Examination of cells by immunofluorescence revealed that c-Cbl is diffusely distributed in the cytoplasm in both unstimulated macrophages and EGF receptor-overexpressing cells and translocated to a more specific compartment of the cell, consistent with the trans-Golgi region, following Fc gamma R clustering and EGF stimulation, respectively. These results suggest that c-Cbl is involved in the signaling pathways utilized by different types of tyrosine kinases.[1]References
- Tyrosine phosphorylation and translocation of the c-cbl protein after activation of tyrosine kinase signaling pathways. Tanaka, S., Neff, L., Baron, R., Levy, J.B. J. Biol. Chem. (1995) [Pubmed]
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