MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells.
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.
Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, ON, Canada.
Emad
E
Heidary Arash
Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, ON, Canada.
Ahmed
A
Shiban
Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, ON, Canada.
Siyuan
S
Song
Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, ON, Canada liliana.attisano@utoronto.ca.
Liliana
0000-0003-4824-2642
L
Attisano
D000217:Acyltransferases; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D055786:Gene Knockout Techniques; D000090683:Hippo Signaling Pathway; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000099317:Hippo Kinases
D000217:Acyltransferases; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; C456659:YY1AP1 protein, human; C108675:TAFAZZIN protein, human; C483047:MARK4 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases

TAZ
; 
YAP
; Hippo pathway; MARK4; breast cancer