Yorkie/YAP Interactors: Fine-Tuning the Hippo Pathway Output

In a canonical view of Hippo signaling, the upstream kinases Hippo/MST and Warts (Wts)/large tumor suppressor (LATS) act as an on/off switch that controls phosphorylation and nuclear access of the key pathway effectors, Yorkie (Yki)/Yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ-binding motif (TAZ). However, studies in flies and mammals have revealed multiple additional regulators that directly associate with Yki/YAP1, often via PPxY motif/WW domain interactions, and fine-tune Hippo pathway activity. In this review, we highlight such "tuners" located at the endosomal membranes, the cell cortex, and in the nucleus, which regulate Yki/YAP1 turnover, nucleocytoplasmic shuttling, and nuclear activity. These factors can set the overall levels of available Yki/YAP1 via sequestration in various subcellular compartments and endosomal/proteasomal degradation. Nuclear "tuners" can direct the Hippo pathway toward specific cellular outcomes, in part through unique transcriptional programs established in concert with Yki/YAP1. Future efforts will be directed at elucidating how the activities of these multiple regulators are coordinated in vivo.