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

[摘要]：Receptor protein tyrosine phosphatase alpha (RPTP alpha)-mediated Src activation is required for survival of tested human colon and oestrogen receptor-negative breast cancer cell lines. To explore whether mutated RPTP alpha participates in human carcinogenesis, we sequenced RPTP alpha cDNAs from five types of human tumours and found splice mutants in similar to 30% of colon, breast, and liver tumours. RPTP alpha 245, a mutant expressed in all three tumour types, was studied further. Although it lacks any catalytic domain, RPTP alpha 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 alpha 245 binding to endogenous RPTP alpha (eRPTP alpha), which decreased eRPTP alpha-Grb2 binding and increased eRPTP alpha dephosphorylation of Src without increasing non-specific eRPTP alpha activity. RPTP alpha 245-eRPTP alpha binding was blocked by Pro210 -> Leu/Pro211 -> Leumutation, consistent with the involvement of the structural 'wedge' that contributes to eRPTP alpha homodimerization. RPTP alpha 245-induced fibroblast transformation was blocked by either Src or eRPTP alpha RNAi, indicating that this required the dephosphorylation of Src by eRPTP alpha. The transformed cells were tumourigenic in nude mice, suggesting that RPTP alpha 245-induced activation of Src in the human tumours may have contributed to carcinogenesis. The EMBO Journal (2011) 30, 3200-3211. doi:10.1038/emboj.2011.212; Published online 1 July 2011

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