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".
Highlights
Nucleocytoplasmic distribution of Yap/TAZ is regulated by the Hippo pathway and the cytoskeleton
Upon Hippo inactivation, Yap/TAZ translocate to the nucleus where they associate with various transcription factors, predominantly with members of the TEAD family, which act as their “nuclear retention factors”[22,23,24,25]
To test whether nuclear translocation of TAZ involves facilitated transport, we studied its localization under circumstances when passive diffusion through the nuclear pore was minimized
Summary
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. Yap/TAZ are primarily controlled at the level of their nuclear accumulation (nucleocytoplasmic shuttling), which is affected by myriads of chemical and mechanical cues, including the integrity of cell–cell contacts (cell density), matrix stiffness, cellular tension, metabolic state, and soluble mediators[12,13,14,15,16,17,18,19] Most of these inputs converge on two distinct, yet interdependent signal-transducing systems: the Hippo pathway and the state of the actomyosin cytoskeleton. We found a critical nuclear export signal (NES), which can be masked by TEAD
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