Journal
CANCER CELL
Volume 38, Issue 1, Pages 115-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.05.019
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Funding
- National Natural Science Foundation of China [81725014, 81822035, 81773212, 21807001, 31630047, 31930026, 81972876, 81902806, 81902389]
- National Key R&D Program of China [2017YFA0504504]
- Science and Technology Commission of Shanghai Municipality [19J1415600, 19PJ1408300]
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- Strategic Priority Research Program [XDB19020202, XDA12010315]
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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.
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