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The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis

文献类型：期刊论文

作者Sun, Yang7; Wei, Henan6; Yu, Wentao6; Gao, Haoran6; Li, Jinhui5; Li, Xiaoyu6; Zhang, Haijiao7; Zhang, Haoen6; Miao, Sen4; Zhao, Lihua4
刊名HEPATOLOGY
出版日期2024-09-25
页码20
ISSN号0270-9139
DOI10.1097/HEP.0000000000001063
通讯作者Jin, Yunyun(yunyunjin@sjtu.edu.cn) ; Zhang, Lei(rayzhang@sibcb.ac.cn)
英文摘要Background and Aims: The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy. Approach and Results: Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3Kmut) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC. Conclusions: Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.
WOS关键词HIPPO PATHWAY ; TEAD/TEF FAMILY ; SIZE-CONTROL ; GROWTH ; PHOSPHORYLATION ; GENE ; PROLIFERATION ; RECRUITMENT ; INHIBITION ; MST2
资助项目National Key Research and Development Program of China[2019YFA0802001] ; National Natural Science Foundation of China[32030025] ; National Natural Science Foundation of China[32293233] ; National Natural Science Foundation of China[32221002] ; National Natural Science Foundation of China[32370751] ; Shanghai Municipal Science and Technology Major Project ; Shanghai Leading Talents Program
WOS研究方向Gastroenterology & Hepatology
语种英语
WOS记录号WOS:001319805000001
出版者LIPPINCOTT WILLIAMS & WILKINS
源URL[http://119.78.100.183/handle/2S10ELR8/313621]  
专题新药研究国家重点实验室
通讯作者Jin, Yunyun; Zhang, Lei
作者单位1.Shanghai Pudong New Area Peoples Hosp, Dept Emergency & Crit Care Med, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, State Key Lab Drug Res, Shanghai, Peoples R China
4.Jining Med Univ, Affiliated Hosp, Dept Pathol, Jining, Peoples R China
5.HuidaGene Therapeut Co Ltd, Shanghai, Peoples R China
6.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci,State Key Lab Cell Bio, Shanghai, Peoples R China
7.Shanghai Jiao Tong Univ, Sheng Yushou Ctr Cell Biol & Immunol, Sch Life Sci & Biotechnol, Dept Genet & Dev Sci, 800 Dongchuan Rd, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Yang,Wei, Henan,Yu, Wentao,et al. The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis[J]. HEPATOLOGY,2024:20.
APA Sun, Yang.,Wei, Henan.,Yu, Wentao.,Gao, Haoran.,Li, Jinhui.,...&Zhang, Lei.(2024).The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis.HEPATOLOGY,20.
MLA Sun, Yang,et al."The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis".HEPATOLOGY (2024):20.

入库方式： OAI收割

来源：上海药物研究所

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