LATS1 K751 acetylation blocks activation of Hippo signalling and switches LATS1 from a tumor suppressor to an oncoprotein  

作　　者：Siyuan Yang Weizhi Xu Cheng Liu Jiaqi Jin Xueying Li Yuhan Jiang Lei Zhang Xianbin Meng Jun Zhan Hongquan Zhang 

机构地区：[1]Department of Human Anatomy,Histology and Embryology,MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs,Peking University Health Science Center,Beijing 100191,China [2]MOE Key Laboratory of Bioinformatics,School of Life Sciences,Tsinghua University,Beijing 100084,China

出　　处：《Science China(Life Sciences)》2022年第1期129-141,共13页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(81730071,81972616,81230051,81472734,31170711 and 81773199);the Ministry of Science and Technology of China(2016YFC1302103 and 2015CB553906);Beijing Natural Science Foundation(7120002 and 7171005);Peking University(BMU2018JC004,BMU20120314 and BMU20130364)。

摘　　要：Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 stability and activation remains elusive.Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4.Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation.Mechanistically,LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation,leading to increased YAP nucleus translocation and promoted target gene expression.Functionally,LATS1-K751 Q,the acetylation mimic mutant potentiated lung cancer cell migration,invasion and tumor growth,whereas LATS1-K751 R,the acetylation deficient mutant inhibited these functions.Taken together,we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.

关 键 词：LATS1 acetylation LATS1 activation and inhibition Hippo signalling pathway lung adenocarcinoma 

分 类 号：R730[医药卫生—肿瘤]