Abstract
The abundance and activity of the membrane-associated nonreceptor tyrosine kinase c-Src are higher in malignant than in nonmalignant cells. Phosphorylation of c-Src by the cytosolic C-terminal Src kinase (Csk) inhibits its activity, thus preventing cellular transformation. In some cancers, however, even an increased abundance of Csk is not sufficient to prevent c-Src-mediated tumorigenesis. Csk is recruited to the plasma membrane by the transmembrane, lipid raft-associated adaptor protein Csk-binding protein (Cbp), which is itself a target of c-Src. Oneyama et al . examined the function of Cbp in c-Src-transformed Csk –/– mouse embryo fibroblasts (MEFs). Retroviral-mediated overexpression of c-Src caused the transformation of Csk –/– MEFs, which was accompanied by a decrease in the abundance of Cbp mRNA and protein. Overexpression of Cbp dose-dependently inhibited c-Src-mediated cellular transformation without inhibiting the activation of c-Src, as measured by Western blotting. Whereas c-Src was distributed in raft and nonraft fractions of transformed cells, overexpression of Cbp resulted in the complete recruitment of c-Src to rafts. Coimmunoprecipitation assays showed a direct association between c-Src and Cbp. Analysis of mutant Cbp proteins showed that its Src homology 2 (SH2) domain-binding sites, but not its Csk-binding site, were needed for Cbp to bind to c-Src and inhibit cellular transformation. Western blotting analysis revealed an inverse correlation between Cbp abundance and the activity of c-Src in various human cancer cell lines. Finally, tumorigenesis in nude mice that received human colon cancer cells expressing Cbp was suppressed compared with that in mice that received the parental cells. In summary, this study suggests that Cbp inhibits the tumorigenic potential of c-Src independently of Csk and that Cbp may serve as a potential anticancer therapeutic target. C. Oneyama, T. Hikita, K. Enya, M.-W. Dobenecker, K. Saito, S. Nada, A. Tarakhovsky, M. Okada, The lipid raft-anchored adaptor protein Cbp controls the oncogenic potential of c-Src. Mol . Cell 30 , 426-436 (2008). [PubMed]
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