RRC ID 78025
Author Tang Y, Fang G, Guo F, Zhang H, Chen X, An L, Chen M, Zhou L, Wang W, Ye T, Zhou L, Nie P, Yu H, Lin M, Zhao Y, Lin X, Yuan Z, Jiao S, Zhou Z.
Title Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer.
Journal Cancer Cell
Abstract Loss of Hippo tumor-suppressor activity and hyperactivation of YAP are commonly observed in cancers. Inactivating mutations of Hippo kinases MST1/2 are uncommon, and it remains unclear how their activity is turned off during tumorigenesis. We identified STRN3 as an essential regulatory subunit of protein phosphatase 2A (PP2A) that recruits MST1/2 and promotes its dephosphorylation, which results in YAP activation. We also identified STRN3 upregulation in gastric cancer correlated with YAP activation and poor prognosis. Based on this mechanistic understanding and aided by structure-guided medicinal chemistry, we developed a highly selective peptide inhibitor, STRN3-derived Hippo-activating peptide, or SHAP, which disrupts the STRN3-PP2Aa interaction and reactivates the Hippo tumor suppressor, inhibits YAP activation, and has antitumor effects in vivo.
Volume 38(1)
Pages 115-128.e9
Published 2020-7-13
DOI 10.1016/j.ccell.2020.05.019
PII S1535-6108(20)30269-5
PMID 32589942
MeSH Amino Acid Sequence Animals Autoantigens / genetics Autoantigens / metabolism* Calmodulin-Binding Proteins / genetics Calmodulin-Binding Proteins / metabolism* Cell Line, Tumor Female Hippo Signaling Pathway Humans Kaplan-Meier Estimate Male Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Middle Aged Peptides / pharmacology* Protein Phosphatase 2 / antagonists & inhibitors Protein Phosphatase 2 / genetics Protein Phosphatase 2 / metabolism* Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* Signal Transduction / drug effects Signal Transduction / genetics Stomach Neoplasms / genetics Stomach Neoplasms / metabolism* Stomach Neoplasms / prevention & control Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism* Xenograft Model Antitumor Assays / methods
IF 26.602
Human and Animal Cells SH-10-TC(RCB1940)