Arhgef7 Promotes Activation of the Hippo Pathway Core Kinase Lats

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.