A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TRCP
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TLDR
It is reported that YAP is phosphorylated by Lats on all of the five consensus HXRXXS motifs and uncovered an intricate mechanism of YAP regulation by the Hippo pathway via both S127 phosphorylation-mediated spatial regulation (nuclear-cytoplasmic shuttling) and the phosphodegron-mediated temporal regulation (degradation).Abstract:
The Yes-associated protein (YAP) transcription coactivator is a key regulator of organ size and a candidate human oncogene. YAP is inhibited by the Hippo pathway kinase cascade, at least in part via phosphorylation of Ser 127, which results in YAP 14-3-3 binding and cytoplasmic retention. Here we report that YAP is phosphorylated by Lats on all of the five consensus HXRXXS motifs. Phosphorylation of Ser 381 in one of them primes YAP for subsequent phosphorylation by CK1delta/epsilon in a phosphodegron. The phosphorylated phosphodegron then recruits the SCF(beta-TRCP) E3 ubiquitin ligase, which catalyzes YAP ubiquitination, ultimately leading to YAP degradation. The phosphodegron-mediated degradation and the Ser 127 phosphorylation-dependent translocation coordinately suppress YAP oncogenic activity. Our study identified CK1delta/epsilon as new regulators of YAP and uncovered an intricate mechanism of YAP regulation by the Hippo pathway via both S127 phosphorylation-mediated spatial regulation (nuclear-cytoplasmic shuttling) and the phosphodegron-mediated temporal regulation (degradation).read more
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The Hippo Signaling Pathway in Development and Cancer
TL;DR: Recent studies suggest that the core Hippo kinase cascade integrates multiple upstream inputs, enabling dynamic regulation of tissue homeostasis in animal development and physiology.
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Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer.
TL;DR: The Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein-coupled receptors, and cellular energy status.
Journal ArticleDOI
Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor Signaling
Fa-Xing Yu,Bin Zhao,Nattapon Panupinthu,Jenna L. Jewell,Ian Lian,Lloyd H. Wang,Jiagang Zhao,Hai-Xin Yuan,Karen Tumaneng,Hairi Li,Xiang-Dong Fu,Gordon B. Mills,Kun-Liang Guan +12 more
TL;DR: This study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the hippo-YAP pathway as a critical signaling branch downstream of GPCR.
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The Biology of YAP/TAZ: Hippo Signaling and Beyond
TL;DR: YAP/TAZ appear at the centerpiece of a signaling nexus by which cells take control of their behavior according to their own shape, spatial location and growth factor context, and are appealing therapeutic targets in cancer and regenerative medicine.
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Mechanisms of Hippo pathway regulation
TL;DR: This review focuses on recent developments in the understanding of the molecular actions of the core Hippo kinase cascade and discusses key open questions in the regulation and function of the Hippo pathway.
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