MK5 Regulates YAP Stability and Is a Molecular Target in YAP-Driven Cancers

Abstract

Transcriptional regulator YAP is activated in multiple human cancers and plays critical roles in tumor initiation, progression, metastasis, and drug resistance. However, therapeutic targeting of the Hippo-YAP pathway has been challenging due to its low druggability and limited knowledge of YAP regulation in cancer. Here we present a functional screen and identify a novel therapeutic target for YAP-driven tumorigenesis. RNAi screening using an oncogenic YAP activation model identified the serine/threonine kinase MK5 as a positive regulator of YAP. MK5 physically interacted with YAP and counteracted CK1δ/ε-mediated YAP ubiquitination and degradation independent of LATS1/2. MK5 kinase activity was essential for protecting YAP from ubiquitin-mediated degradation and cytoplasmic retention. Downregulating MK5 expression inhibited the survival of YAP-activated cancer cell lines and mouse xenograft models. MK5 upregulation was associated with high levels of YAP expression and poor prognosis in clinical tumor samples, confirming its important role for YAP activity in human cancer. These results uncover MK5 as a novel factor that regulates YAP stability, and targeting the YAP degradation pathway controlled by MK5 is a potential strategy for suppressing YAP activity in cancer. SIGNIFICANCE: These findings reveal MK5 is a novel kinase that regulates YAP in a LATS-independent manner and can be targeted for cancer therapy.