The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1
The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1
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DOI：
10.1038/sj.onc.1208445
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发表时间：
2005-03-17
期刊：
影响因子：
8
通讯作者：
Silljé, HHW
中科院分区：
文献类型：
--
作者：
Chan, EH;Nousiainen, M;Silljé, HHW
疣蛋白激酶(Wts)/Lats蛋白激酶最初在黑腹果蝇中被发现，并被认为与另外两种果蝇蛋白Hippo （Hpo）和Salvador （Sav）一起调节细胞周期退出和凋亡。在哺乳动物中，已经描述了两个候选的疣/Lats同源物，称为Lats1和Lats2，并且在小鼠中靶向破坏Lats1会增加肿瘤的形成。然而，我们对人类Lats激酶的功能和调控知之甚少。在这里，我们报道了人类Mst2， ste20家族成员和声称的Hpo同源物，磷酸化并激活Lats1和Lats2。缺失分析显示Lats1的调控是通过c端催化结构域进行的。在这个区域内，两个调节磷酸化位点被质谱鉴定。这些位点，激活环中的S909和疏水基序中的T1079，在进化过程中高度保守。此外，研究还发现Mst2与果蝇同源基因hWW45之间存在直接相互作用。这些结果表明mst2样激酶通过进化保守的调控途径调控Lats激酶的活性。尽管这一途径在哺乳动物中的功能尚不清楚，但令人感兴趣的是，在果蝇中，它与发育和组织稳态有关。
Originally identified in Drosophila melanogaster, the Warts(Wts)/Lats protein kinase has been proposed to function with two other Drosophila proteins, Hippo (Hpo) and Salvador (Sav), in the regulation of cell cycle exit and apoptosis. In mammals, two candidate Warts/Lats homologs, termed Lats1 and Lats2, have been described, and the targeted disruption of LATS1 in mice increases tumor formation. Little, however, is known about the function and regulation of human Lats kinases. Here we report that human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2. Deletion analysis revealed that regulation of Lats1 occurs through the C-terminal, catalytic domain. Within this domain, two regulatory phosphorylation sites were identified by mass spectrometry. These sites, S909 in the activation loop and T1079 within a hydrophobic motif, have been highly conserved during evolution. Moreover, a direct interaction was observed between Mst2 and hWW45, a putative ortholog of Drosophila Sav. These results indicate that Mst2-like kinases regulate Lats kinase activities in an evolutionarily conserved regulatory pathway. Although the function of this pathway remains poorly understood in mammals, it is intriguing that, in Drosophila, it has been linked to development and tissue homeostasis.