Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2.

ABSTRACT: Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may therefore display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphoryl

SUBMITTER: Bulos ML 

PROVIDER: S-EPMC10153145 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature