Abstract
YAP and TAZ, the Hippo signal-regulated transcriptional co-activators, play crucial roles in morphogenesis and organogenesis. Here we report that the YAP/TAZ activities are stimulated upon complex formation with Parafibromin, which undergoes tyrosine phosphorylation and dephosphorylation by kinases such as PTK6 and phosphatases such as SHP2, respectively. Furthermore, TAZ and the Wnt effector β-catenin interact cooperatively with tyrosine-dephosphorylated Parafibromin, which synergistically stimulates the co-activator functions of TAZ and β-catenin. On the other hand, YAP is selectively activated through binding with tyrosine-phosphorylated Parafibromin, which does not interact with β-catenin and thus cannot co-activate YAP and β-catenin. These findings indicate that Parafibromin inversely regulates the activities of YAP and TAZ depending on its tyrosine phosphorylation status. They also suggest that YAP and TAZ exert their redundant and non-redundant biological actions through mutually exclusive interaction with Parafibromin, which is regulated by a balance of kinase and phosphatase activities toward Parafibromin.