Identification of novel protein tyrosine phosphatases (PTPs) regulating the Hippo pathway in tumorigenesis
The Hippo signaling pathway is a tumor suppressor pathway which plays key roles in normal organ size control through regulation of cell proliferation and cell death. Deregulation of the Hippo pathway leads to excessive cell proliferation and loss of cell contact inhibition, which is observed in tumorigenesis and metastasis. Although the regulation of the Hippo pathway by protein kinases is extensively studied, how the Hippo pathway is regulated by protein phosphatases is largely unknown. In this study, we first did a screening by using a LATS biosensor (LATS-BS), a YAP /TAZ activity reporter (STBS-Luc) and a PTP (Protein Tyrosine Phosphatase) library. Based on the result of two parallel screenings, I have identified many novel PTP regulators of the Hippo pathway. Further experiments were performed to validate the result of the screening. Of all candidates, PTPN12 was selected for further study as it is a tumor suppressor gene that is mutated in a variety of cancers including breast cancer. Recently PTPN12 was shown to play a role as a master regulator of oncogenic Receptor Tyrosine kinases (RTKs), therefore it is a novel regulator of the Hippo pathway in breast cancer cells. We further demonstrated that PTPN12 regulates the Hippo pathway through inhibition of the oncogenic function of the main effector of the Hippo pathway, YAP. Interestingly, we demonstrated that loss of PTPN12 increases cell proliferation in MCF10A mammary cells in a Hippo-dependent manner. Altogether, our findings provide useful information on the roles of PTP-Hippo interactions in breast cancer biology and therapy.