Activation of Src and transformation by an RPTP? splice mutant found in human tumours.

ABSTRACT: Receptor protein tyrosine phosphatase ? (RPTP?)-mediated Src activation is required for survival of tested human colon and oestrogen receptor-negative breast cancer cell lines. To explore whether mutated RPTP? participates in human carcinogenesis, we sequenced RPTP? cDNAs from five types of human tumours and found splice mutants in ?30% of colon, breast, and liver tumours. RPTP?245, a mutant expressed in all three tumour types, was studied further. Although it lacks any catalytic domain, RPTP?245 expression in the tumours correlated with Src tyrosine dephosphorylation, and its expression in rodent fibroblasts activated Src by a novel mechanism. This involved RPTP?245 binding to endogenous RPTP? (eRPTP?), which decreased eRPTP?-Grb2 binding and increased eRPTP? dephosphorylation of Src without increasing non-specific eRPTP? activity. RPTP?245-eRPTP? binding was blocked by Pro210 ? Leu/Pro211 ? Leu mutation, consistent with the involvement of the structural 'wedge' that contributes to eRPTP? homodimerization. RPTP?245-induced fibroblast transformation was blocked by either Src or eRPTP? RNAi, indicating that this required the dephosphorylation of Src by eRPTP?. The transformed cells were tumourigenic in nude mice, suggesting that RPTP?245-induced activation of Src in the human tumours may have contributed to carcinogenesis.

SUBMITTER: Huang J 

PROVIDER: S-EPMC3160186 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature