Murine polyomavirus small T antigen (PyST) regulates cell cycle, cell survival, apoptosis, differentiation and cooperates with middle T antigen (MT) to transform primary cells in vitro and in vivo. Like all polyoma virus T antigens, PyST functions largely via its interactions with host cell proteins. Here we show that PyST binds both Yes-associated proteins YAP1 and YAP2, integral parts of the Hippo signaling pathway, which is a subject of increasing interest in human cancer. The transcription factor TEAD, which is a known target of YAP, is also found in PyST complexes. PyST enhanced YAP association with protein phosphatase 2A (PP2A) leading to decreased YAP phosphorylation. PyST increased YAP levels by decreasing its degradation. This effect was mediated by a reduction in YAP association with βTRCP, which is known to regulate YAP turnover in a phosphorylation dependent manner. Genetic analysis has identified PyST mutants defective in YAP binding. These mutants demonstrated that YAP binding is important for PyST to block myoblast differentiation and to synergize with the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) to promote cell death in 3T3L1 preadipocytes placed under differentiation conditions. In addition to YAP binding, both of these phenotypes require PyST binding to PP2A.