Mechanisms of kinase-dependent regulation of Hippo tumor suppressor signaling
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The Hippo pathway is frequently deregulated in human cancers, but mutations and deletions of core signalome members are rare, suggesting that our understanding of its upstream regulators remains incomplete. A focused RNAi-based kinome screen identified novel candidate regulators of Hippo signaling, including STK25 and MST4. Here, we characterize the kinase STK25 as a novel upstream activator of LATS signaling. Depletion of STK25 was found to significantly reduce YAP phosphorylation in response to Hippo-activating stimuli, with consequent increases in YAP/TAZ activity and increased proliferation and resistance to cell cycle arrest. Mechanistically, STK25 activates LATS independently of the canonical MST/MAP4K axis, wherein STK25 directly promotes the phosphorylation of the LATS kinase activation loop in the absence of a preceding hydrophobic motif phosphorylation event. This differentiates STK25 from all other identified Hippo kinases to date, which may explain why singular loss of this kinase cannot be compensated for by the presence of other Hippo kinases. We also find that loss of STK25 increases YAP/TAZ signaling in vivo and that this promotes organ overgrowth in murine models. Interestingly, STK25 is frequently focally deleted in a spectrum of human cancers, suggesting that its loss might represent a way by which cancer cells functionally inactivate Hippo signaling. We also report that STK25 may be a novel regulator of mTOR signaling, as loss of STK25 hyper-activates mTOR signaling in response to amino acids and growth factors, but not to energy stresses. Interestingly, we find that MST4, a kinase closely related to STK25, appears to have highly context-specific Hippo regulatory functions; loss of MST4 was found to modulate Hippo signaling only in non-polarized cell lines, suggesting that polarity-responsive subcellular localization of MST4 may dictate its ability to interact with Hippo signaling. Lastly, we describe a novel role for Hippo signaling as a surveillance system for abnormal prolongation of mitosis, in which the LATS kinases regulate cell fate following abnormal mitosis via its control over p53-p21 signaling and YAP/TAZ signaling. This work thus identifies new roles and mechanisms by which kinases interact in the context of this major tumor suppressor pathway to control cellular processes critical to physiologic homeostasis.