The Hippo pathway is a critical regulator of tissue size, and aberrations in pathway regulation lead to cancer. MST1/2 and LATS1/2 kinases comprise the core of the pathway that, in association with adaptor proteins SAV and MOB, functions in a sequential manner to phosphorylate and inhibit the transcription factors YAP and TAZ. Here we identify mammalian MARK family members as activators of YAP/TAZ. We show that depletion of MARK4 in MDA‐MB‐231 breast cancer cells results in the loss of nuclear YAP/TAZ and decreases the expression of YAP/TAZ targets. We demonstrate that MARK4 can bind to MST and SAV, leading to their phosphorylation, and that MARK4 expression attenuates the formation of a complex between MST/SAV and LATS, which depends on the kinase activity of MARK4. Abrogation of MARK4 expression using siRNAs and CRISPR/Cas9 gene editing attenuates the proliferation and migration of MDA‐MB‐231 cells. Our results show that MARK4 acts as a negative regulator of the Hippo kinase cassette to promote YAP/TAZ activity and that loss of MARK4 restrains the tumorigenic properties of breast cancer cells.
Hippo signaling regulates tissue size and aberrations in the pathway can lead to cancer. This study identifies MARK family kinases as negative regulators of Hippo signaling by promoting the activity of YAP and TAZ via the inhibition of the Hippo kinase cascade.
Abrogation of MARK4 expression promotes YAP/TAZ phosphorylation and degradation.
MARK4 phosphorylates the Hippo core cassette components MST and SAV, thereby disrupting LATS‐mediated phosphorylation of YAP/TAZ.
Loss of MARK4 attenuates cell proliferation and migration of breast cancer cells independently of MST and SAV.
- Received March 29, 2016.
- Revision received December 22, 2016.
- Accepted January 6, 2017.
- © 2017 The Authors
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