Abstract
Nucleocytoplasmic distribution of Yap/TAZ is regulated by the Hippo pathway and the cytoskeleton. While interactions with cytosolic and nuclear "retention factors" (14-3-3 and TEAD) are known to control their localization, fundamental aspects of Yap/TAZ shuttling remain undefined. It is unclear if translocation occurs only by passive diffusion or via mediated transport, and neither the potential nuclear localization and efflux signals (NLS, NES) nor their putative regulation have been identified. Here we show that TAZ cycling is a mediated process and identify the underlying NLS and NES. The C-terminal NLS, representing a new class of import motifs, is necessary and sufficient for efficient nuclear uptake via a RAN-independent mechanism. RhoA activity directly stimulates this import. The NES lies within the TEAD-binding domain and can be masked by TEAD, thereby preventing efflux. Thus, we describe a RhoA-regulated NLS, a TEAD-regulated NES and propose an improved model of nucleocytoplasmic TAZ shuttling beyond "retention".