Activation of Src and transformation by an RPTPα splice mutant found in human tumours
Activation of Src and transformation by an RPTPα splice mutant found in human tumours
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人类肿瘤中发现的 RPTPα 剪接突变体对 Src 的激活和转化
DOI：
10.1038/emboj.2011.212
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发表时间：
2011-08-03
期刊：
影响因子：
11.4
通讯作者：
Zheng, Xinmin
中科院分区：
文献类型：
--
作者：
Huang, Jian;Yao, Ling;Zheng, Xinmin
受体蛋白酪氨酸磷酸酶α（RPTP α）介导的Src激活是所测试的人结肠癌和雌激素受体阴性乳腺癌细胞系存活所必需的。为了探索突变的RPTP α是否参与人类致癌作用，我们对来自五种类型的人类肿瘤的RPTP α cDNA进行了测序，并在30%的结肠、乳腺和肝脏肿瘤中发现了类似的剪接突变体。RPTP α 245是一种在所有三种肿瘤类型中表达的突变体，我们对它进行了进一步研究。虽然它缺乏任何催化结构域，RPTP α 245在肿瘤中的表达与Src酪氨酸去磷酸化相关，其在啮齿动物成纤维细胞中的表达通过一种新的机制激活Src。这涉及RPTP α 245与内源性RPTP α（eRPTP α）的结合，这降低了eRPTP α-Grb 2结合，并增加了Src的eRPTP α去磷酸化，而不增加非特异性eRPTP α活性。RPTP α 245-eRPTP α结合被Pro210 -> Leu/Pro211 -> Leumutation阻断，这与参与eRPTP α同源二聚化的结构“楔形”一致。RPTP α 245诱导的成纤维细胞转化被Src或eRPTP α RNAi阻断，表明这需要eRPTP α使Src去磷酸化。转化的细胞在裸鼠中具有致瘤性，这表明RPTP α 245诱导的人类肿瘤中Src的激活可能有助于致癌作用。The EMBO Journal（2011）30，3200-3211. doi：10.1038/doj.2011.212; 2011年7月1日在线发布
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