Protein kinase Cα activation switches YAP1 from TEAD‐mediated signaling to p73‐mediated signaling

Yes‐associated protein 1 (YAP1) interacts with TEAD transcription factor in the nucleus and upregulates TEAD‐target genes. YAP1 is phosphorylated by large tumor suppressor (LATS) kinases, the core kinases of the Hippo pathway, at 5 serine residues and is sequestered and degraded in the cytoplasm. In human cancers with the dysfunction of the Hippo pathway, YAP1 becomes hyperactive and confers malignant properties to cancer cells. We have observed that cold shock induces protein kinase C (PKC)‐mediated phosphorylation of YAP1. PKC phosphorylates YAP1 at 3 serine residues among LATS‐mediate phosphorylation sites. Importantly, PKC activation recruits YAP1 to the cytoplasm even in LATS‐depleted cancer cells and reduces the cooperation with TEAD. PKC activation induces promyelocytic leukemia protein‐mediated SUMOylation of YAP1. SUMOylated YAP1 remains in the nucleus, binds to p73, and promotes p73‐target gene transcription. Bryostatin, a natural anti‐neoplastic reagent that activates PKC, induces YAP1/p73‐mediated apoptosis in cancer cells. Bryostatin reverses malignant transformation caused by the depletion of LATS kinases. Therefore, bryostatin and other reagents that activate PKC are expected to control cancers with the dysfunction of the Hippo pathway. Protein kinase C (PKC)‐mediated phosphorylation of YAP1 weakens the interaction with TEAD independently of the Hippo pathway and promotes the cooperation with p73 to induce apoptosis. PKC activation may be useful to suppress malignant properties in cancers with the dysfunction of the Hippo pathway.