6iur | pdb_00006iur
A phosphatase complex STRN3-PP2Aa
Structural highlights
Function2AAA_HUMAN The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Required for proper chromosome segregation and for centromeric localization of SGOL1 in mitosis.[1] Publication Abstract from PubMedLoss 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. Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer.,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 Cancer Cell. 2020 Jun 10. pii: S1535-6108(20)30269-5. doi:, 10.1016/j.ccell.2020.05.019. PMID:32589942[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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