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 localiza-tion of the transcriptional regulators Yap and Taz to inhibit tran-scription. Here, we identify the multidomain-containing guanine nucleotide exchange factor (GEF) Arhgef7, or bPix, as a positive Hippo pathway regulator. We show that bPix, 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. bPix is required downstream of both cell density sensing and actin cytoskeletal rearrangements, and we demon-strate that loss of bPix expression in normal mammary epithelial cells strongly reduces Yap/Taz phosphorylation, promotes nuclear localization and increases target gene expression. Conversely, increased expression of bPIX 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 prolif-eration. These studies thus define bPix as a key component that links the Hippo kinase cassette to Yap/Taz in response to multiple upstream Hippo pathway activators.