p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor-suppressor function mediated by p190A RhoGAP
Hanyue Ouyang,
Shuang Wu,
Wangji Li,
Michael J. Grey,
Wenchao Wu,
Steen H. Hansen
Affiliations
Hanyue Ouyang
GI Cell Biology Laboratory, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China
Shuang Wu
Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
Wangji Li
GI Cell Biology Laboratory, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Michael J. Grey
GI Cell Biology Laboratory, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Wenchao Wu
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China
Steen H. Hansen
GI Cell Biology Laboratory, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: 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.
