<br>MST1/MST2 蛋白激酶：调节和生理作用,Biochemistry

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MST1/MST2 蛋白激酶：调节和生理作用
Biochemistry ( IF 2.9 ) Pub Date : 2016-09-26 00:00:00 , DOI: 10.1021/acs.biochem.6b00763
Jacob A Galan _{1,

2,

3} , Joseph Avruch _{1,

2,

3}

Affiliation

MST1 和 MST2 蛋白激酶包含 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，它们最显着的特征是在羧基末端附近存在一种独特的螺旋结构，称为 SARAH 结构域；该片段允许 MST1/MST2 与包含 SARAH 结构域的其他多肽（非催化多肽 RASSF1-6 和 Sav1/WW45）同二聚和异二聚。早期研究强调了 MST1/MST2 在过表达时诱导细胞凋亡的强大能力，以及在任何刺激引发的细胞凋亡过程中内源性 MST1/MST2 多肽转化为组成型活性、半胱天冬酶切割的催化片段。后来，在非凋亡、静止的成年肝细胞以及正在进行终末分化的细胞中鉴定出了 MST1 的裂解、组成型活性形式，在这些细胞中，MST1 的存在是维持这些细胞状态所必需的。全长 MST1/MST2 的生理调节由其非催化 SARAH 结构域伙伴的可用性控制。与 Sav1/WW45 的相互作用将 MST1/MST2 招募到肿瘤抑制途径中，其中它磷酸化并激活 Sav1 结合蛋白激酶 Lats1/Lats2，这是 Yap1 和 TAZ 致癌转录调节因子的有效抑制剂。 T 细胞中与 Rap1-GTP 结合蛋白 RASSF5B (Nore1B/RAPL) 的组成型相互作用会招募 MST1（尤其是）和 MST2 作为 Rap1 控制 T 细胞粘附和迁移的效应器，这是对免疫监视和反应至关重要的程序；人类 MST1 的功能缺失突变会导致严重的免疫缺陷。 MST1 和 MST2 还受到其他蛋白激酶的调节，其中 TAO1 呈正向调节，Par1、SIK2/3、Akt 和 cRaf1 呈负向调节。越来越多的候选 MST1/MST2 底物表明 MST1/MST2 的全部生理程序和对病理生理学的贡献仍有待阐明。

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MST1/MST2 Protein Kinases: Regulation and Physiologic Roles

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.

更新日期：2016-09-26

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