School of Biological Sciences, University of Reading, Whiteknights Campus, Harborne Building, Reading RG6 6AS, U.K.
Biochem J. 2013 Aug 15;454(1):13-30. doi: 10.1042/BJ20130219.
The GCKIII (germinal centre kinase III) subfamily of the mammalian Ste20 (sterile 20)-like group of serine/threonine protein kinases comprises SOK1 (Ste20-like/oxidant-stress-response kinase 1), MST3 (mammalian Ste20-like kinase 3) and MST4. Initially, GCKIIIs were considered in the contexts of the regulation of mitogen-activated protein kinase cascades and apoptosis. More recently, their participation in multiprotein heterocomplexes has become apparent. In the present review, we discuss the structure and phosphorylation of GCKIIIs and then focus on their interactions with other proteins. GCKIIIs possess a highly-conserved, structured catalytic domain at the N-terminus and a less-well conserved C-terminal regulatory domain. GCKIIIs are activated by tonic autophosphorylation of a T-loop threonine residue and their phosphorylation is regulated primarily through protein serine/threonine phosphatases [especially PP2A (protein phosphatase 2A)]. The GCKIII regulatory domains are highly disorganized, but can interact with more structured proteins, particularly the CCM3 (cerebral cavernous malformation 3)/PDCD10 (programmed cell death 10) protein. We explore the role(s) of GCKIIIs (and CCM3/PDCD10) in STRIPAK (striatin-interacting phosphatase and kinase) complexes and their association with the cis-Golgi protein GOLGA2 (golgin A2; GM130). Recently, an interaction of GCKIIIs with MO25 has been identified. This exhibits similarities to the STRADα (STE20-related kinase adaptor α)-MO25 interaction (as in the LKB1-STRADα-MO25 heterotrimer) and, at least for MST3, the interaction may be enhanced by cis-autophosphorylation of its regulatory domain. In these various heterocomplexes, GCKIIIs associate with the Golgi apparatus, the centrosome and the nucleus, as well as with focal adhesions and cell junctions, and are probably involved in cell migration, polarity and proliferation. Finally, we consider the association of GCKIIIs with a number of human diseases, particularly cerebral cavernous malformations.
哺乳动物 Ste20 样丝氨酸/苏氨酸蛋白激酶家族的 GCKIII（生殖中心激酶 III）亚家族包括 SOK1（Ste20 样/氧化应激反应激酶 1）、MST3（哺乳动物 Ste20 样激酶 3）和 MST4。最初，GCKIII 被认为在丝裂原激活的蛋白激酶级联和细胞凋亡的调节中发挥作用。最近，它们参与多蛋白异源复合物的情况变得明显。在本综述中，我们讨论了 GCKIII 的结构和磷酸化，然后重点讨论了它们与其他蛋白质的相互作用。GCKIII 具有高度保守的、结构域化的 N 端催化结构域和不太保守的 C 端调节结构域。GCKIII 通过 T 环苏氨酸残基的持续自磷酸化而被激活，其磷酸化主要通过蛋白丝氨酸/苏氨酸磷酸酶[特别是 PP2A（蛋白磷酸酶 2A）]来调节。GCKIII 调节结构域高度无序，但可以与更结构化的蛋白质相互作用，特别是 CCM3（脑静脉畸形 3）/PDCD10（程序性细胞死亡 10）蛋白。我们探讨了 GCKIII（和 CCM3/PDCD10）在 STRIPAK（条纹状蛋白相互作用的磷酸酶和激酶）复合物中的作用及其与顺式高尔基体蛋白 GOLGA2（高尔基体 A2；GM130）的关联。最近，鉴定了 GCKIII 与 MO25 的相互作用。这类似于 STRADα（STE20 相关激酶衔接子α）-MO25 相互作用（如在 LKB1-STRADα-MO25 异三聚体中），至少对于 MST3，其调节域的顺式自磷酸化可能增强了相互作用。在这些各种异源复合物中，GCKIII 与高尔基体、中心体和细胞核以及粘着斑和细胞连接相关，并可能参与细胞迁移、极性和增殖。最后，我们考虑了 GCKIII 与许多人类疾病的关联，特别是脑静脉畸形。
