MST4调控Hippo信号通路及胃癌的功能机制

MST4 kinase is a member of the GCKIII (germinal center kinase III) subfamily of STE-20 serine / threonine protein kinases family, involved in physiological activities such as cell growth, apoptosis, cell polarity and cell migration, and also closely related to tumorigenesis. Hippo signaling pathway, highly conserved in evolution, plays important roles in multiple biological processes such as cell proliferation and apoptosis. Our previous studies（J Exp Med）have been made preliminarily to explore the molecular mechanism of Hippo signaling pathway involved in tumorigenesis of gastric cancer. However, the specific function and signal switch of the MST4 on Hippo signaling pathway in tumorigenesis regulation remain to be unclear. Here, we investigate the signaling mechanism of MST4 kinase mediated on tumorigenesis of gastric cancer by taking advantage of Hippo signaling pathway as breakthrough point. The preliminarily studies showed that down-regulation of MST4 expression was found in the tissues from gastric cancer, and negatively related with YAP downstream gene expression, indicating MST4 regulated Hippo signaling pathway involved in occurrence and development of gastric cancer. Therefore, to explore the key signal control node, our project will focus on elucidating possible molecular linkages among MST4, Hippo pathway, and gastric cancer, which would provide theoretical basis and optional strategy for drug design and gastric cancer therapy.

MST4是丝氨酸／苏氨酸蛋白激酶家族STE-20中生发中心激酶GCKⅢ亚家族的成员，参与细胞的生长、凋亡、极化与迁移等生理活动，且与肿瘤的发生紧密相关。Hippo通路在进化上高度保守，在调控细胞增殖与凋亡等一系列生命过程中扮演重要角色。申请人前期针对Hippo通路在胃癌发生中分子机制展开探索，取得了阶段性成果（J Exp Med）。鉴于MST4调控胃癌发生的功能和信号机制仍未完全明晰，申请人拟以Hippo通路为研究切入点，深入研究MST4介导胃癌发生的信号机制。初步研究显示，MST4在胃癌组织中呈现下调趋势，且与YAP下游基因表达明显负相关，提示MST4可能通过Hippo通路介导胃癌的发生发展。因此，本项目将着重理清MST4、Hippo通路以及胃癌发生三者之间的分子联系，挖掘其中关键的信号调控节点，为胃癌诊断和药物治疗提供理论基础。

MST4是丝氨酸／苏氨酸蛋白激酶家族STE-20中生发中心激酶GCKⅢ亚家族的成员，参与细胞的生长、凋亡、极化与迁移等生理活动，且与肿瘤的发生紧密相关。Hippo通路在进化上高度保守，在调控细胞增殖与凋亡等一系列生命过程中扮演重要角色。鉴于MST4调控胃癌发生的功能和信号机制仍未完全明晰，项目负责人以Hippo通路为研究切入点，主要围绕MST4调控Hippo信号通路及胃癌发生的功能机制方面展开研究。研究表明MST4在胃癌组织中呈现下调趋势，且与YAP下游基因表达明显负相关。我们发现MST4能够直接与Hippo通路的YAP结合，并且能够磷酸化YAP。通过体外激酶实验获得了磷酸化位点T83，并制备了能够识别该位点磷酸化的抗体，进一步验证了MST4野生型和突变体在体内对YAP的磷酸化以及功能，其T83磷酸化可以显著抑制YAP与importin α介导的入核复合物结合，最终导致其在细胞质内聚集。因此，本项目中将着重理清了MST4、Hippo通路以及胃癌发生三者之间的分子联系，挖掘其中关键的信号调控节点，为胃癌诊断和药物治疗提供理论基础。