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EMBO Rep. 2017 Mar;18(3):420-436. doi: 10.15252/embr.201642455. Epub 2017 Feb 9.

MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells.

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Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, ON, Canada.
Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, ON, Canada


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.


TAZ ; YAP ; Hippo pathway; MARK4; breast cancer

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