title: Arhgef7 promotes activation of the Hippo pathway core kinase Lats.
abstract: The Hippo pathway regulates tissue growth and organ size, and inactivation contributes to cancer. Signals flow through Mst/Lats kinases, which phosphorylate and promote cytoplasmic localization of the transcriptional regulators Yap and Taz to inhibit transcription. Here, we identify the multidomain-containing guanine nucleotide exchange factor (GEF) Arhgef7, or βPix, as a positive Hippo pathway regulator. We show that βPix, which localizes to the cytoplasm, binds both Lats and Yap/Taz and thereby promotes Lats-mediated phosphorylation of Yap/Taz in a GEF-independent manner. βPix is required downstream of both cell density sensing and actin cytoskeletal rearrangements, and we demonstrate that loss of βPix expression in normal mammary epithelial cells strongly reduces Yap/Taz phosphorylation, promotes nuclear localization and increases target gene expression. Conversely, increased expression of βPIX in breast cancer cell lines re-couples the Hippo kinase cassette to Yap/Taz, promoting localization of Yap/Taz to the cytoplasm and inhibiting cell migration and proliferation. These studies thus define βPix as a key component that links the Hippo kinase cassette to Yap/Taz in response to multiple upstream Hippo pathway activators.
authors.affiliation: Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Emad
authors.initials: E
authors.lastname: Heidary Arash
authors.affiliation: Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Ki Myung
authors.initials: KM
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Shiban
authors.affiliation: Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON, Canada liliana.attisano@utoronto.ca.
authors.forename: Liliana
authors.initials: L
authors.lastname: Attisano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: C576606:ARHGEF7 protein, human; D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D064067:Rho Guanine Nucleotide Exchange Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Arhgef7; Hippo; Lats; Yap/Taz; mechanotransduction