MST1/MST2 Protein Kinases: Regulation and Physiologic Roles.
MST1/MST2 Protein Kinases: Regulation and Physiologic Roles.
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DOI：
10.1021/acs.biochem.6b00763
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发表时间：
2016-10-04
期刊：
影响因子：
2.9
通讯作者：
Avruch J
中科院分区：
文献类型：
--
作者：
Galan JA;Avruch J
MST1和MST2蛋白激酶组成GCK-II蛋白激酶亚家族。除了与酿酒酵母蛋白激酶Ste20相关的氨基末端激酶催化结构域外，它们最显著的特征是在羧基末端附近存在一个独特的螺旋结构，称为SARAH结构域；该片段允许MST1/MST2与含有SARAH结构域的其他多肽、非催化多肽RASSF1-6和Sav1/WW45进行同二聚和异二聚。早期的研究强调了MST1/MST2在过表达时诱导细胞凋亡的强大能力，以及内源性MST1/MST2多肽在任何刺激引发的细胞凋亡过程中转化为组成活性的caspase裂解催化片段。后来，在非凋亡的、静止的成年肝细胞以及处于终末分化的细胞中发现了断裂的、组成活性形式的MST1，在这些细胞中，它的存在是维持这些细胞状态所必需的。全长MST1/MST2的生理调控是由其非催化性SARAH结构域伙伴的可用性控制的。与Sav1/WW45的相互作用将MST1/MST2招募到一个肿瘤抑制通路，其中它磷酸化并激活Sav1结合的蛋白激酶Lats1/Lats2，这是Yap1和TAZ致癌转录调节因子的有效抑制剂。与Rap1- gtp结合蛋白RASSF5B （Nore1B/RAPL）在T细胞中的组成性相互作用招募MST1（特别是）和MST2，作为Rap1控制T细胞粘附和迁移的效应物，这是免疫监视和应答的关键程序；人类MST1的功能突变丧失导致严重的免疫缺陷。MST1和MST2也受其他蛋白激酶的调控，受TAO1的正调控，受Par1、SIK2/3、Akt和cRaf1的负调控。候选MST1/MST2底物名单的不断增加表明，MST1/MST2的全部生理程序及其对病理生理的贡献仍有待阐明。
The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1–6 and Sav1/WW45. Early studies emphasized the potent ability of MST1/MST2 to induce apoptosis upon being overexpressed, as well as the conversion of the endogenous MST1/MST2 polypeptides to constitutively active, caspase-cleaved catalytic fragments during apoptosis initiated by any stimulus. Later, the cleaved, constitutively active form of MST1 was identified in nonapoptotic, quiescent adult hepatocytes as well as in cells undergoing terminal differentiation, where its presence is necessary to maintain those cellular states. The physiologic regulation of full length MST1/MST2 is controlled by the availability of its noncatalytic SARAH domain partners. Interaction with Sav1/WW45 recruits MST1/MST2 into a tumor suppressor pathway, wherein it phosphorylates and activates the Sav1-bound protein kinases Lats1/Lats2, potent inhibitors of the Yap1 and TAZ oncogenic transcriptional regulators. A constitutive interaction with the Rap1-GTP binding protein RASSF5B (Nore1B/RAPL) in T cells recruits MST1 (especially) and MST2 as an effector of Rap1’s control of T cell adhesion and migration, a program crucial to immune surveillance and response; loss of function mutation in human MST1 results in profound immunodeficiency. MST1 and MST2 are also regulated by other protein kinases, positively by TAO1 and negatively by Par1, SIK2/3, Akt, and cRaf1. The growing list of candidate MST1/MST2 substrates suggests that the full range of MST1/MST2’s physiologic programs and contributions to pathophysiology remains to be elucidated.