Defining the role of the kinase MST4 in the context of the Hippo tumor suppressor pathway
Mauricio, Ian Paolo Morelos
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The Hippo tumor suppressor pathway is a highly conserved signaling cascade initially identified in Drosophila which acts to regulate organ size and cellular proliferation. The Hippo pathway integrates extracellular and intracellular cues such as cytoskeletal tension, growth factor signaling, and nutrient availability to ultimately activate the LATS kinases. Activated LATS kinases then inhibit the downstream oncoproteins YAP and TAZ via a phosphorylation-dependent mechanism, in which 14-3-3 dependent cytoplasmic sequestration promotes YAP/TAZ degradation via the ubiquitin-proteasome pathway. Upstream regulators of LATS activation remain poorly characterized. MST1/2, which are mammalian orthologs of the Drosophila Hpo kinase, appear to be largely dispensable for Hippo pathway activation, suggesting evolutionary redundancy arising as a result of divergence and diversification of MSTs in human cells. We identified MST4, a close cousin of MST1/2, as a potential novel regulator of Hippo signaling in non-transformed, non-polarized human cells. Loss of MST4 resulted in decreased YAP phosphorylation in response to actin disruption, and also increased total abundance of TAZ, but interestingly did not affect levels of phosphorylated LATS. Overexpression of wild-type MST4 activated Hippo signaling and promoted TAZ degradation, which correlated to the effects MST4 had on levels of HIF1α. MST4 may be playing a previously unappreciated role in regulation of Hippo tumor suppressor signaling via a LATS1/2-independent pathway.