| Literature DB >> 32589942 |
Yang Tang1, Gemin Fang2, Fenghua Guo3, Hui Zhang4, Xiaoxu Chen2, Liwei An5, Min Chen5, Li Zhou6, Wenjia Wang4, Tiantian Ye4, Lei Zhou7, Pingping Nie4, Haijun Yu7, Moubin Lin8, Yun Zhao4, Xinhua Lin9, Zengqiang Yuan10, Shi Jiao11, Zhaocai Zhou12.
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.Entities:
Keywords: Hippo-YAP signaling pathway; STRN3-derived Hippo-activating peptide (SHAP); gastric cancer; recover tumor-suppressor activity; therapeutic targeting of phosphatase
Year: 2020 PMID： 32589942 DOI： 10.1016/j.ccell.2020.05.019
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743