Identification of STK25 as a direct activator of LATS signaling

LATS kinases integrate numerous cellular cues to restrict the oncoproteins YAP/TAZ in a phosphorylation-dependent fashion as part of the Hippo tumor suppressor pathway, yet upstream activators of LATS kinases remain incompletely characterized. We performed a focused RNAi-based kinome screen and identified the kinase STK25 as a previously uncharacterized activator of LATS. We demonstrate that loss of STK25 blunts the ability of cells to activate Hippo signaling and is sufficient to significantly increase levels of active YAP/TAZ to enhance cellular proliferation. In contrast to all known kinase activators of LATS, which phosphorylate the hydrophobic motif of LATS kinases to stimulate auto-phosphorylation, STK25 directly phosphorylates the activation loop motif of LATS. Interestingly, STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a major mechanism by which tumors are able to functionally impair the Hippo tumor suppressor pathway.