The Role of Hippo Pathway in Mitosis and Cancer

The Hippo signaling pathway has been recently elucidated as a tumor suppressor pathway controlling cell proliferation and apoptosis. The core of this pathway is a kinase cascade which contains MST1/2 (Mammalian sterile 20-like kinase 1/2), LATS1/2 (large tumor suppressor 1/2) and downstream effector named Yes-associated protein (YAP). MST1/2 transduce their kinase activity mainly through directly phosphorylating LATS1/2. Once phosphorylated and activated, LATS1/2 subsequently phosphorylate and inhibit YAP from translocating to nucleus. Current studies involving the Hippo pathway focus on determining its oncogenic role in various organs/tissues. While those studies provide important insight into the tumor suppressor properties of this pathway, the underlying molecular mechanisms through which the Hippo components exert their oncogenic/suppressing function are poorly understood. Our study found that the adaptor protein Ajuba (recent found as a positive regulator of YAP oncogenic activity) and MST2 (the core kinase in the Hippo pathway), are phosphorylated by CDK1 in mitosis via novel sites. We further characterized the phospho-regulation of Ajuba and MST2 in mitosis and examined the functional significance of the phosphorylation. Mutation of those phosphorylation sites impact cell proliferation in vitro and tumorigenesis in vivo. Our group has recently shown that the downstream effector of the Hippo pathway, YAP, is phosphorylated during mitosis and activated in a CDK1-dependent manner. In this study, we generated, for the first time, a doxycycline-inducible mouse model in which active YAP was specifically expressed in the pancreas. Interestingly, this mouse model develops pancreatic acinar-to-ductal metaplasia (ADM) in two weeks. Moreover, significant body weight loss and food intake decrease were observed after YAP induction in the pancreas, which are characteristics of cachexia. Cachexia is a wasting syndrome associated with typical types of cancer, particularly the gastrointestinal tract cancer and lung cancer. Among those cancer types, pancreatic ductal adenocarcinoma (PDAC) has the highest incidence of cancer cachexia. Therefore, our study suggests a potential role of YAP in pancreatic cancer-associated cachexia (CAC)