Gene

Kinase

Cell biology

Protein phosphatase 2

Biotechnology

Biology

Signal transduction

Cancer research

Biochemistry

Phosphorylation

Downregulation and upregulation

Phosphatase

Genetics

In vivo

Internal medicine

Dephosphorylation

Protein subunit

Hippo signaling pathway

Hyperactivation

Medicine

Chemistry

Carcinogenesis

Suppressor

Cancer

Cancer cell

Cancer Cell

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.

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