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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway and plays a pro-oncogenic role in pancreatic cancer
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The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway and plays a pro-oncogenic role in pancreatic cancer

机译：MST4-MOB4复合物破坏了Hippo-YAP途径中的MST1-MOB1复合物并在胰腺癌中起促癌作用

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The mammalian STE20-like protein kinase 1 (MST1)–MOB kinase activator 1 (MOB1) complex has been shown to suppress the oncogenic activity of Yes-associated protein (YAP) in the mammalian Hippo pathway, which is involved in the development of multiple tumors, including pancreatic cancer (PC). However, it remains unclear whether other MST–MOB complexes are also involved in regulating Hippo–YAP signaling and have potential roles in PC. Here, we report that mammalian STE20-like kinase 4 (MST4), a distantly related ortholog of the MST1 kinase, forms a complex with MOB4 in a phosphorylation-dependent manner. We found that the overall structure of the MST4–MOB4 complex resembles that of the MST1–MOB1 complex, even though the two complexes exhibited opposite biological functions in PC. In contrast to the tumor-suppressor effect of the MST1–MOB1 complex, the MST4–MOB4 complex promoted growth and migration of PANC-1 cells. Moreover, expression levels of MST4 and MOB4 were elevated in PC and were positively correlated with each other, whereas MST1 expression was down-regulated. Because of divergent evolution of key interface residues, MST4 and MOB4 could disrupt assembly of the MST1–MOB1 complex through alternative pairing and thereby increased YAP activity. Collectively, these findings identify the MST4–MOB4 complex as a noncanonical regulator of the Hippo–YAP pathway with an oncogenic role in PC. Our findings highlight that although MST–MOB complexes display some structural conservation, they functionally diverged during their evolution.
机译：哺乳动物STE20样蛋白激酶1（MST1）–MOB激酶激活剂1（MOB1）复合物已显示抑制哺乳动物河马途径中Yes相关蛋白（YAP）的致癌活性，这参与了多种河马的发展。肿瘤，包括胰腺癌（PC）。但是，尚不清楚其他MST-MOB复合物是否也参与调节Hippo-YAP信号传导并在PC中具有潜在作用。在这里，我们报告哺乳动物STE20样激酶4（MST4），MST1激酶的远缘直系同源物，以磷酸化依赖性方式与MOB4形成复合物。我们发现MST4-MOB4复合物的总体结构类似于MST1-MOB1复合物，尽管这两种复合物在PC中表现出相反的生物学功能。与MST1-MOB1复合物的肿瘤抑制作用相反，MST4-MOB4复合物促进了PANC-1细胞的生长和迁移。此外，PC中MST4和MOB4的表达水平升高并且彼此正相关，而MST1的表达下调。由于关键界面残基的进化不同，MST4和MOB4可以通过替代配对破坏MST1-MOB1复合物的组装，从而增加YAP活性。总的来说，这些发现确定MST4-MOB4复合体是Hippo-YAP途径的非典型调节剂，在PC中具有致癌作用。我们的发现强调，尽管MST-MOB复合物显示出一定的结构保守性，但它们在进化过程中的功能却有所不同。

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