Nuclear Import and Export of YAP and TAZ

SIMPLE SUMMARY: YAP and TAZ are transcriptional activators, which play critical roles in the regulation of cell/organ growth and regeneration. Accordingly, they are important mediators and modulators of cancer formation and spread, impacting a wide range of processes from cancer stem cell differentiation through the control of proliferation, phenotype determination, and migration, till the induction of antitumor drug resistance. These widespread activities are due to their profound effect on gene expression. Importantly, to exert these physiological and pathological functions, they must enter the nucleus, while for the termination of their transcriptional effects, they must exit. However, the critical structural requirements (nuclear localization signal and nuclear export signal) as well as their passageway(s) and mechanism(s) for crossing the nuclear pore are only beginning to emerge. This review summarizes the current knowledge about the nuclear traffic of YAP and TAZ, a fundamental, novel, and potentially exploitable aspect of their biology. ABSTRACT: Yes-associated Protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding Motif (TAZ) are major regulators of gene transcription/expression, primarily controlled by the Hippo pathway and the cytoskeleton. Integrating an array of chemical and mechanical signals, they impact growth, differentiation, and regeneration. Accordingly, they also play key roles in tumorigenesis and metastasis formation. Their activity is primarily regulated by their localization, that is, Hippo pathway- and/or cytoskeleton-controlled cytosolic or nuclear sequestration. While many details of such prevailing retention models have been elucidated, much less is known about their actual nuclear traffic: import and export. Although their size is not far from the cutoff for passive diffusion through the nuclear pore complex (NPC), and they do not contain any classic nuclear localization (NLS) or nuclear export signal (NES), evidence has been accumulating that their shuttling involves mediated and thus regulatable/targetable processes. The aim of this review is to summarize emerging information/concepts about their nucleocytoplasmic shuttling, encompassing the relevant structural requirements (NLS, NES), nuclear transport receptors (NTRs, karyophererins), and NPC components, along with the potential transport mechanisms and their regulation. While dissecting retention vs. transport is often challenging, the emerging picture suggests that YAP/TAZ shuttles across the NPC via multiple, non-exclusive, mediated mechanisms, constituting a novel and intriguing facet of YAP/TAZ biology.