A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).

By Bin Zhao, Li Li, K. Tumaneng, Cun-Yu Wang, K. Guan. Genes & Development, 2010

1,411 citations recorded by the source corpus.

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).

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e28e7ff5510cb248ef49cefb1815d7907fd14e1c

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In Cell Biology

1. K. Guan
2. Fa-Xing Yu
3. S. Piccolo
4. Bin Zhao
5. M. Cordenonsi
6. S. Dupont
7. Z. Meng
8. Xaralabos Varelas

In Molecular Biology

1. K. Guan
2. Bin Zhao
3. Fa-Xing Yu
4. S. Piccolo
5. M. Cordenonsi
6. Duojia Pan
7. Xaralabos Varelas
8. Z. Meng

Citations in the corpus

• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, neutral): “In addition, phosphorylation of YAP on serine 381 (S381) triggers a subsequent phosphorylation by casein kinase 1 (CK1d/ε) and activation of a phosphodegron, resulting in recruitment of SCFbeta-TRCP E3 ligase, ubiquitination, and proteasomal degradation of YAP (Zhao et al., 2010).”
• Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. (2011, background): “Phosphorylation on YAP S381 primes subsequent phosphorylation by another kinase, possibly casein kinase 1 (CK1d/e), activating a phosphodegron and causing the recruitment of SCFb-TRCP E3 ubiquitin ligase, leading to YAP ubiquitination and degradation (Zhao et al. 2010b).”
• The Hippo signaling pathway in stem cell biology and cancer (2014, neutral): “Phosphorylated YAP is sequestered in the cytoplasm via binding to 14-3-3 and is degraded in a ubiquitin-proteasome-dependent manner, which depends on phosphorylation of YAP Ser381 and Ser384 [23].”
• Mechanisms of Hippo pathway regulation (2016, background): “Moreover, LATS-induced phosphorylation triggers subsequent phosphorylation of YAP/TAZ by Casein kinase 1δ/ε and recruitment of the SCF E3 ubiquitin ligase, leading to eventual YAP/TAZ ubiquitination and degradation (Liu et al. 2010; Zhao et al. 2010).”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “Phosphorylation of S381 has been linked to regulation of YAP/TAZ protein stability, as it primes for additional phosphorylation by CK1 kinases; this generates a “phosphodegron” recognized by -transducin repeatcontaining protein -TRCP, a key adaptor for the SCF E3 ubiquitin ligases, leading to YAP/TA”
• The Hippo Signaling Pathway in Development and Cancer (2010, background): “Both S381-mediated YAP degradation and the previously described S127-mediated nuclear-cytoplasmic translocation are critical for YAP inactivation because both phosphorylation sites must be mutated before YAP can transform NIH 3T3 cells (Zhao et al., 2010).”
• The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal (2011, neutral): “In mammals, YAP and TAZ are phosphorylated by Lats1/2 in vitro and in vivo”
• SCF/β-TrCP Promotes Glycogen Synthase Kinase 3-Dependent Degradation of the Nrf2 Transcription Factor in a Keap1-Independent Manner (2011, background): “This DSGIS sequence is identical to that found in the erythropoietin receptor (31) and the Yes-associated protein (52).”
• Regulation of the Hippo-YAP pathway by G-protein coupled receptor signaling (2012, background): “Genetically modified mouse models demonstrate that 780 Cell 150, 780–791, August 17, 2012 ª2012 Elsevier Inc. function of the Hippo pathway in organ size regulation is conserved in mammals (reviewed in Zhao et al., 2010a).”
• Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. (2012, background): “Lats1/2 directly phosphorylateYes-associated protein (YAP) on serine residues in five consensusHXRXXS motifs (Zhao et al. 2010).”
• The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease (2014, background): “A consequence of these modifications is the recruitment of the β-TrCP/SCF ubiquitin ligase, which facilitates TAZ/YAP ubiquitylation and degradation (Liu et al., 2010; Zhao et al., 2010).”
• The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain (2012, background): “As mentioned above, the Hippo pathway represses YAP activity both by promoting its cytoplasmic sequestration through phosphorylation of serine 127 (1, 9) and by promoting its proteasomal degradation through phosphorylation of serine 381 (12).”
• The Hippo pathway: regulators and regulations. (2013, background): “The requirement for MST1/2 to activate Lats1/2 might be cell type-dependent.”