Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP

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<jats:p>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 <jats:italic>Drosophila</jats:italic>, 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 <jats:italic>Yap</jats:italic><jats:sup><jats:italic>S112A</jats:italic></jats:sup> knock-in mutation in the endogenous <jats:italic>Yap</jats:italic> locus. The <jats:italic>Yap</jats:italic><jats:sup><jats:italic>S112A</jats:italic></jats:sup> 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 <jats:italic>Yap</jats:italic><jats:sup><jats:italic>S112A</jats:italic></jats:sup> 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.</jats:p>

収録刊行物

  • Genes & Development

    Genes & Development 29 (12), 1285-1297, 2015-06-15

    Cold Spring Harbor Laboratory

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