Viral Based Design: Remodeling the Hippo Pathway from Tumor Suppression to Oncogenesis

During the process of evolution viruses have learned to tailor cellular functions to their own needs. Due to the frugal nature of viral design, viral regulatory proteins are small, multipurpose, and efficient. For this reason, viruses curate a treasure-trove of molecular information for the synthetic biologist, providing a glimpse into a natural process of ?reverse-engineering? of cellular functions. The polyomavirus middle T antigen (PyMT) induces oncogenic transformation by hijacking cellular signaling effectors. Activation of the tyrosine kinase, c-Src, is a key step, imperative for viral oncogenesis. However, the underlying mechanism of Src activation by PyMT remains elusive. We addressed this fundamental question by examining the virus-host interaction between PyMT and the Hippo tumor suppressor pathway. The Hippo pathway is a major regulator of cellular proliferation. PyMT physically interacts with the Hippo pathway effector Taz (WWTR1). In proliferating cells Taz is nuclear and coactivates the pro-oncogenic TEAD transcription factors. Taz phosphorylation by Hippo pathway core kinase, Lats, leads to Taz nuclear exclusion and a consequent downregulation of TEAD coactivation. We found that Taz was required for transformation by PyMT in a counter-intuitive manner. Despite the cells undergoing oncogenic proliferation, Taz was exclusively cytoplasmic in the presence of PyMT, an observation expected to have rendered Taz deprived of its reported pro-proliferative function. Indeed, PyMT markedly inhibited TEAD coactivation by Taz, an event associated with tumor suppression. We resolved the molecular basis of the enigmatic Taz cytoplasmic retention by PyMT by demonstrating that PyMT activated the Lats tumor suppressor kinase leading to Taz nuclear exclusion. Next, we searched a role for cytosolic Taz in PyMT oncogenesis and identified Shp2, a phospho-tyrosine phosphatase, as an important player. Taz regulates Shp2 subcellular localization via physical interaction. PyMT induced cytosolic localization of Taz and Shp2. We demonstrate how PyMT designs a new network in oncogenesis where, counter- intuitively, the tumor suppressor Hippo pathway plays a critical role. We propose that understanding viruses is of great value in designing sophisticated synthetic modules.