The MST4-MOB4 complex disrupts the MST1-MOB1 complex in the Hippo-YAP pathway and plays a pro-oncogenic role in pancreatic cancer

doi:10.1074/jbc.RA118.003279

	The MST4-MOB4 complex disrupts the MST1-MOB1 complex in the Hippo-YAP pathway and plays a pro-oncogenic role in pancreatic cancer
	Chen, Min 1; Zhang, Hui 1; Shi, Zhubing 1; Li, Yehua 1; Zhang, Xiaoman 1; Gao, Ziyang 1; Zhou, Li2 ; Ma, Jian 1; Xu, Qi 1; Guan, Jingmin 1; Cheng, Yunfeng 3,4; Jiao, Shi 1; Zhou, Zhaocai1,2
	2018-09-14
发表期刊	JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN	0021-9258
卷号	293 期号:37 页码:14455-14469
发表状态	已发表
DOI	10.1074/jbc.RA118.003279
摘要	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.
关键词	Hippo pathway crystal structure molecular evolution pancreatic cancer MST1 (Mammalian Sterile 20-like kinase 1) MOB4 MST4 STRIPAK Hippo signaling
收录类别	EI ; SCIE ; SCI
语种	英语
资助项目	China Postdoctoral Science Foundation[2018T110414]
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000444671500024
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
EI入藏号	20183805832446
EI主题词	Diseases ; Mammals ; Tumors
EI分类号	Biological Materials and Tissue Engineering:461.2
WOS关键词	ORGAN SIZE CONTROL ; CELL-PROLIFERATION ; KINASE MST4 ; PROMOTES APOPTOSIS ; STRIPAK COMPLEXES ; DENDRITIC SPINES ; HUMAN MOB1 ; PROTEIN ; PHOSPHORYLATION ; ACTIVATION
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/27814
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_周兆才组生命科学与技术学院_硕士生
通讯作者	Jiao, Shi; Zhou, Zhaocai
作者单位	1.Univ Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, Chinese Acad Sci,State Key Lab Cell Biol, Shanghai 200031, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Fudan Univ, Zhongshan Hosp, Dept Hematol, Shanghai 200032, Peoples R China 4.Fudan Univ, Zhongshan Hosp, Inst Clin Sci, Shanghai 200032, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Chen, Min,Zhang, Hui,Shi, Zhubing,et al. The MST4-MOB4 complex disrupts the MST1-MOB1 complex in the Hippo-YAP pathway and plays a pro-oncogenic role in pancreatic cancer[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2018,293(37):14455-14469.
APA	Chen, Min.,Zhang, Hui.,Shi, Zhubing.,Li, Yehua.,Zhang, Xiaoman.,...&Zhou, Zhaocai.(2018).The MST4-MOB4 complex disrupts the MST1-MOB1 complex in the Hippo-YAP pathway and plays a pro-oncogenic role in pancreatic cancer.JOURNAL OF BIOLOGICAL CHEMISTRY,293(37),14455-14469.
MLA	Chen, Min,et al."The MST4-MOB4 complex disrupts the MST1-MOB1 complex in the Hippo-YAP pathway and plays a pro-oncogenic role in pancreatic cancer".JOURNAL OF BIOLOGICAL CHEMISTRY 293.37(2018):14455-14469.