河马信号通路
原癌基因酪氨酸蛋白激酶Src
细胞生物学
酪氨酸磷酸化
磷酸化
癌症研究
生物
酪氨酸激酶
受体酪氨酸激酶
信号转导
癌变
癌症
遗传学
作者
Yuan Su,Xinyan Ji,Xiaolei Cao,Xiaoming Dai,Li Xu,Hongxia Zhao,Xiaohong Guo,Huan Yan,Haitao Zhang,Chengzhan Zhu,Qi Zhou,Mei Tang,Zongping Xia,Li Li,Yu‐Sheng Cong,Sheng Ye,Tingbo Liang,Xin‐Hua Feng,Bin Zhao
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2017-09-14
卷期号:77 (18): 4868-4880
被引量:108
标识
DOI:10.1158/0008-5472.can-17-0391
摘要
Abstract 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.
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