The Hippo signaling pathway converges on YAP to regulate growth, 
differentiation, and regeneration. Previous studies with overexpressed proteins 
have shown that YAP is phosphorylated by its upstream kinase, Lats1/2, on 
multiple sites, including an evolutionarily conserved 14-3-3-binding site whose 
phosphorylation is believed to inhibit YAP by excluding it from the nucleus. 
Indeed, nuclear localization of YAP or decreased YAP phosphorylation at this 
site (S168 in Drosophila, S127 in humans, and S112 in mice) is widely used in 
current literature as a surrogate of YAP activation even though the 
physiological importance of this phosphorylation event in regulating endogenous 
YAP activity has not been defined. Here we address this question by introducing 
a Yap(S112A) knock-in mutation in the endogenous Yap locus. The Yap(S112A) mice 
are surprisingly normal despite nuclear localization of the mutant YAP protein 
in vivo and profound defects in cytoplasmic translocation in vitro. 
Interestingly, the mutant Yap(S112A) mice show a compensatory decrease in YAP 
protein levels due to increased phosphorylation at a mammalian-specific 
phosphodegron site on YAP. These findings reveal a robust homeostatic mechanism 
that maintains physiological levels of YAP activity and caution against the 
assumptive use of YAP localization alone as a surrogate of YAP activity.