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. 2020 Jul 13;38(1):115-128.e9.
doi: 10.1016/j.ccell.2020.05.019. Epub 2020 Jun 25.

Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer

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Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer

Yang Tang et al. Cancer Cell. .
Free article

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.

Keywords: Hippo-YAP signaling pathway; STRN3-derived Hippo-activating peptide (SHAP); gastric cancer; recover tumor-suppressor activity; therapeutic targeting of phosphatase.

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Conflict of interest statement

Declaration of Interests Z.Z., S.J., Y.T., G.F., W.W., and Y.Z. have filed a patent (CN111100189A) for the SHAP in China.

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