蛋白质酪氨酸磷酸酶RPTPα对新底物Ago2蛋白的去磷酸化调控研究

早期的研究发现，受体型蛋白质酪氨酸磷酸酶RPTPα通过特异催化c-Src蛋白的C - 末端527位酪氨酸残基去磷酸化，激活c-Src并诱发细胞发生恶性转化，揭示RPTPα具有激活癌基因的潜能。目前已知的RPTPα催化底物主要是c-Src激酶家族成员（如c-Src, Fyn, Yes)，而对其它底物的鉴定则少有研究。我们近期利用底物陷阱技术（substrate-trapping techniques) 初步证明Ago2蛋白是RPTPα的一个新底物。已知Ago2蛋白是RNA诱导沉默复合物（RNA-induced silencing complex, RISC）的核心组分，通过促进miRNA的加工成熟，进而抑制靶基因的表达。本课题拟在前期发现基础上，通过一系列细胞实验、动物模型等深入研究磷酸酶RPTPα对Ago2蛋白去磷酸化作用的分子机制以及RPTPα—Ago2调控模式在肿瘤发生中的作用。

RPTPα was the first to demonstrate that PTPs can dephosphorylate tyrosine 527 of c-Src and activate c-Src . Generally, RPTPα has been shown to dephosphorylate and activate Src family kinases (SFKs), thus functions as an oncogene. However , little is known about its other substrates in physiological condition. Our present data show that using substrate-trapping techniques, Ago2 protein, one key element in RNA-induced silencing complex (RISC ) and miRNA maturation, was identified to interact with RPTPα and be dephosphorylated directly , which imply that Ago2 may be a novel substrate of RPTPα. In this study, we try to clarify the molecular mechanism of Ago2 dephosphorylation by RPTPα , and elucidate the role of RPTPα—Ago2 signaling in tumor cell line and animal model. All the results should help us to better know relationship between tumorigenesis and RPTPα-related signaling pathway.