Identification of the kinase STK25 as an upstream activator of LATS signaling

Sanghee Lim, Nicole Hermance, Tenny Mudianto, Hatim M. Mustaly, Ian Paolo Morelos Mauricio, Marc A. Vittoria, Ryan J. Quinton, Brian W. Howell, Hauke Cornils, Amity L. Manning and Neil J. Ganem ()
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Sanghee Lim: Boston University School of Medicine
Nicole Hermance: Worcester Polytechnic Institute
Tenny Mudianto: Boston University School of Medicine
Hatim M. Mustaly: Boston University School of Medicine
Ian Paolo Morelos Mauricio: Boston University School of Medicine
Marc A. Vittoria: Boston University School of Medicine
Ryan J. Quinton: Boston University School of Medicine
Brian W. Howell: SUNY Upstate Medical University
Hauke Cornils: Evotec
Amity L. Manning: Worcester Polytechnic Institute
Neil J. Ganem: Boston University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract The Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of the Hippo pathway is common in tumors, mutations in core pathway components are rare. Thus, understanding how tumor cells inactivate Hippo signaling remains a key unresolved question. Here, we identify the kinase STK25 as an activator of Hippo signaling. We demonstrate that loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation, even under normally growth-suppressive conditions both in vitro and in vivo. Notably, STK25 activates LATS by promoting LATS activation loop phosphorylation independent of a preceding phosphorylation event at the hydrophobic motif, which represents a form of Hippo activation distinct from other kinase activators of LATS. STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a common mechanism by which tumor cells functionally impair the Hippo tumor suppressor pathway.

Date: 2019
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DOI: 10.1038/s41467-019-09597-w

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