The characterisation of LATS2 kinase regulation in Hippo-YAP signalling
The characterisation of LATS2 kinase regulation in Hippo-YAP signalling
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DOI：
10.1016/j.cellsig.2016.02.012
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发表时间：
2016-05-01
影响因子：
4.8
通讯作者：
Hergovich, Alexander
中科院分区：
文献类型：
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作者：
Hoa, Lily;Kulaberoglu, Yavuz;Hergovich, Alexander
通过控制YAP1原癌蛋白，河马信号在癌症相关过程中发挥重要作用。目前的证据表明，河马激酶MST1/2与MOB1支架蛋白一起促进活性MOB1/LATS复合体的形成，该复合体磷酸化，从而抑制YAP1。然而，MST1/2-MOB1-LATS信号的调控机制目前还没有得到充分的研究。因此，我们研究了LATS2变体，这些变体带有特定的修饰，可以模拟磷酸化的得失和/或取消MOB1/LATS2的相互作用。我们发现LATS2的Ser872T-loop和Thr1041疏水基序(HM)的磷酸化是LATS2激活所必需的。MST1/2磷酸化Thr1041上的LATS2，但不磷酸化Ser872，而MOB1与LATS2结合支持这两种磷酸化事件。值得注意的是，LATS2-PIF是包含PRK2 HM的LATS2变体，它作为一种高活性的LATS2蛋白，有效地磷酸化YAP1并抑制YAP1的转录共活性。LATS2-PIF的这种抑制功能依赖于LATS2激酶的活性，而MOB1/LATS2和YAP1/LATS2复合体的形成是不必要的，这表明LATS2激酶活性的提高足以对抗YAP1。综上所述，我们对LATS2变体的特征揭示了对河马信号中EATS激酶的调节的新见解。(C)2016 Elsevier Inc.保留所有权利。
By controlling the YAP1 proto-oncoprotein Hippo signalling plays important roles in cancer-associated processes. Current evidence suggests that the Hippo kinases MST1/2 together with the MOB1 scaffold protein promote the formation of active MOB1/LATS complexes which phosphorylate and thereby inhibit YAP1. However, the regulatory mechanisms of MST1/2-MOB1-LATS signalling are currently underinvestigated. Therefore, we studied LATS2 variants carrying specific modifications that mimic gain or loss of phosphorylation and/or abolish MOB1/LATS2 interactions. We discovered that Ser872 T-loop and Thr1041 hydrophobic motif (HM) phosphorylation of LATS2 is essential for LATS2 activation. MST1/2 phosphorylate LATS2 on Thr1041, but not Ser872, while MOB1 binding to LATS2 supports both phosphorylation events. Significantly, LATS2-PIF, a LATS2 variant containing the PRK2 HM, acts as a hyperactive LATS2 kinase that efficiently phosphorylates YAP1 and inhibits the transcriptional co-activity of YAP1. This inhibitory function of LATS2-PIF is dependent on LATS2 kinase activity, while MOB1/LATS2 and YAP1/LATS2 complex formation is dispensable, suggesting that elevated LATS2 kinase activity can be sufficient to oppose YAP1. Taken together, our characterisation of LATS2 variants uncovers novel insights into the regulation of EATS kinases in Hippo signalling. (C) 2016 Elsevier Inc. All rights reserved.