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.

通常在癌症中观察到河马肿瘤抑制剂活性的丧失和YAP的过度活化。Hippo激酶MST1 / 2的失活突变并不常见，目前尚不清楚在肿瘤发生过程中如何关闭其活性。我们确定STRN3是募集MST1 / 2并促进其去磷酸化的蛋白磷酸酶2A（PP2A）的必需调节亚基，从而导致YAP激活。我们还发现胃癌中STRN3的上调与YAP激活和预后不良有关。基于这种机理的理解，并借助结构指导的药物化学，我们开发了一种高度选择性的肽抑制剂，STRN3衍生的Hippo激活肽或SHAP，可破坏STRN3-PP2Aa的相互作用并重新激活Hippo抑癌剂，抑制YAP激活并具有抗肿瘤作用体内。