Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1.
Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1.
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DOI：
10.1158/0008-5472.can-17-0391
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发表时间：
2017-09
期刊：
影响因子：
11.2
通讯作者：
Y. Si;Xinyan Ji;Xiaolei Cao;Xiaoming Dai;Lingyi Xu;Hongxia Zhao;Xiaocan Guo;Huan Yan;Haitao Zha
中科院分区：
文献类型：
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作者：
Y. Si;Xinyan Ji;Xiaolei Cao;Xiaoming Dai;Lingyi Xu;Hongxia Zhao;Xiaocan Guo;Huan Yan;Haitao Zha
Hippo通路调节细胞增殖、凋亡和干细胞自我更新，其在动物模型中的失活导致器官增大，随后发生肿瘤。Hippo通路失调发生在许多人类癌症中，但其潜在机制尚未完全了解。在这里，我们报告酪氨酸磷酸化的海马通路肿瘤抑制LATS 1作为其调节细胞粘附的机制。酪氨酸激酶文库筛选鉴定Src为直接磷酸化LATS 1多个残基的激酶，导致减弱的Mob激酶激活剂结合和激酶结构域中底物结合口袋的结构改变。细胞基质粘附部分通过Src介导的磷酸化和LATS 1的抑制激活Hippo通路效应子转录辅激活因子雅普。异常Src激活取消了LATS 1的肿瘤抑制活性，并以YAP依赖的方式诱导肿瘤发生。人乳腺癌组织中Src蛋白水平与LATS 1靶位点上活性去磷酸化雅普的积累相关。这些发现揭示了Src对LATS 1的酪氨酸磷酸化是通过细胞粘附调节Hippo通路的一种新机制，并表明Src活化是肿瘤发生中雅普失调的一个潜在原因。Cancer Res; 77（18）; 4868-80.©2017 AACR.
The Hippo pathway regulates cell proliferation, apoptosis, and stem cell self-renewal, and its inactivation in animal models causes organ enlargement followed by tumorigenesis. Hippo pathway deregulation occurs in many human cancers, but the underlying mechanisms are not fully understood. Here, we report tyrosine phosphorylation of the Hippo pathway tumor suppressor LATS1 as a mechanism underlying its regulation by cell adhesion. A tyrosine kinase library screen identified Src as the kinase to directly phosphorylate LATS1 on multiple residues, causing attenuated Mob kinase activator binding and structural alteration of the substrate-binding pocket in the kinase domain. Cell matrix adhesion activated the Hippo pathway effector transcription coactivator YAP partially through Src-mediated phosphorylation and inhibition of LATS1. Aberrant Src activation abolished the tumor suppressor activity of LATS1 and induced tumorigenesis in a YAP-dependent manner. Protein levels of Src in human breast cancer tissues correlated with accumulation of active YAP dephosphorylated on the LATS1 target site. These findings reveal tyrosine phosphorylation of LATS1 by Src as a novel mechanism of Hippo pathway regulation by cell adhesion and suggest Src activation as an underlying reason for YAP deregulation in tumorigenesis. Cancer Res; 77(18); 4868-80. ©2017 AACR.