YAP was first identified based on its ability to associate with the SH3 domain of Yes. It also binds to other SH3 domain-containing proteins such as Nck, Crk, Src, and Abl. In addition to the SH3 binding motif, YAP contains a PDZ interaction motif, a coiled-coil domain, and WW domains. While initial studies of YAP all pointed towards a role in anchoring and targeting to specific subcellular compartments, subsequent studies showed that YAP is a transcriptional co-activator by virtue of its WW domain interacting with the PY motif of the transcription factor PEBP2 and other transcription factors. In its capacity as a transcriptional co-activator, YAP is now widely recognized as a central mediator of the Hippo Pathway, which plays a fundamental and widely conserved role in regulating tissue growth and organ size. Phosphorylation at multiple sites by LATS kinases promotes YAP translocation from the nucleus to the cytoplasm, where it is sequestered through association with 14-3-3 proteins. These LATS-driven phosphorylation events serve to prime YAP for subsequent phosphorylation by CK1δ/ε in an adjacent phosphodegron, triggering proteasomal degradation of YAP.
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