p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor-suppressor function mediated by p190A RhoGAP

ARHGAP35, which encodes p190A RhoGAP (p190A), is a major cancer gene. p190A is a tumor suppressor that activates the Hippo pathway. p190A was originally cloned via direct binding to p120 RasGAP (RasGAP). Here, we determine that interaction of p190A with the tight-junction-associated protein ZO-2 is dependent on RasGAP. We establish that both RasGAP and ZO-2 are necessary for p190A to activate large tumor-suppressor (LATS) kinases, elicit mesenchymal-to-epithelial transition, promote contact inhibition of cell proliferation, and suppress tumorigenesis. Moreover, RasGAP and ZO-2 are required for transcriptional modulation by p190A. Finally, we demonstrate that low ARHGAP35 expression is associated with shorter survival in patients with high, but not low, transcript levels of TJP2 encoding ZO-2. Hence, we define a tumor-suppressor interactome of p190A that includes ZO-2, an established constituent of the Hippo pathway, and RasGAP, which, despite strong association with Ras signaling, is essential for p190A to activate LATS kinases. [Display omitted] •ARHGAP35 is a human TSG encoding p190A RhoGAP, an activator of the Hippo pathway•Interactions of p190A with RasGAP and ZO-2 are necessary to activate LATS kinases•RasGAP/ZO-2 are required for effects of p190A on gene expression and tumorigenesis•ARHGAP35 expression in LUAD samples correlates strongly with Hippo signaling In this work, Ouyang et al. define interactions of p190A with p120 RasGAP and the tight-junction protein ZO-2 that are necessary for p190A to activate the Hippo pathway, modulate gene transcription, elicit mesenchymal-to-epithelial transition, promote contact inhibition of cell proliferation, and suppress tumorigenesis in a xenograft mouse model.