International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438.
J Biol Chem. 2012 Nov 16;287(47):39812-23. doi: 10.1074/jbc.M112.406520. Epub 2012 Sep 28.
Pro-tumorigenic function of the p38 kinase plays a critical role in human cholangiocarcinogenesis. However, the underlying mechanism remains incompletely understood. Here, we report that c-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), contributes to the pro-tumorigenic ability of p38 in human cholangiocarcinoma cells. Both p38 and c-Met promote the proliferation and invasion of human cholangiocarcinoma cells. Importantly, inhibition or knockdown of p38 decreased the basal activation of c-Met. Tyrosine phosphatase inhibitor studies revealed that p38 promotes the activity of c-Met, at least in part, by inhibiting dephosphorylation of the receptor. Moreover, density enhanced phosphatase-1 (DEP-1) is involved in p38-mediated inhibiting dephosphorylation of c-Met. Furthermore, p38 inhibits the degradation of c-Met. Taken together, these data provide a potential mechanism to explain how p38 promotes human cholangiocarcinoma cell proliferation and invasion. We propose that the link between p38 and c-Met is implicated in the progression of human cholangiocarcinoma.
p38 激酶的促肿瘤功能在人类胆管癌发生中起着关键作用。然而，其潜在的机制尚不完全清楚。在这里，我们报告 c-Met，即肝细胞生长因子（HGF）的酪氨酸激酶受体，有助于 p38 在人胆管癌细胞中的促肿瘤能力。p38 和 c-Met 均促进人胆管癌细胞的增殖和侵袭。重要的是，p38 的抑制或敲低降低了 c-Met 的基础激活。酪氨酸磷酸酶抑制剂研究表明，p38 通过抑制受体的去磷酸化至少部分地促进 c-Met 的活性。此外，密度增强磷酸酶-1（DEP-1）参与了 p38 介导的 c-Met 去磷酸化抑制。此外，p38 抑制 c-Met 的降解。总之，这些数据提供了一个潜在的机制来解释 p38 如何促进人胆管癌细胞的增殖和侵袭。我们提出，p38 和 c-Met 之间的联系与人类胆管癌的进展有关。
