A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TRCP
A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TRCP
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DOI：
10.1101/gad.1843810
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发表时间：
2010-01-01
影响因子：
10.5
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
--
作者：
Zhao, Bin;Li, Li;Guan, Kun-Liang
Yes相关蛋白（雅普）转录辅激活因子是器官大小的关键调节因子，也是一个候选的人类癌基因。雅普被Hippo途径激酶级联抑制，至少部分通过Ser 127的磷酸化，这导致雅普14-3-3结合和细胞质保留。在这里，我们报告说，雅普是磷酸化的Lats的所有五个共识HXRXXS基序。其中一个引发雅普中Ser 381的磷酸化，随后在磷酸降解决定子中被CK 1 δ/β磷酸化。然后磷酸化的磷酸降解决定子招募SCF β-TRCP E3遍在蛋白连接酶，该酶催化雅普蛋白遍在蛋白化，最终导致雅普蛋白降解。磷酸化降解和Ser 127磷酸化依赖性易位协同抑制雅普的致癌活性。我们的研究确定了CK 1 delta/CK 2作为雅普的新调节因子，并揭示了Hippo通路通过S127磷酸化介导的空间调节（核质穿梭）和磷酸化介导的时间调节（降解）来调节雅普的复杂机制。
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 CK1 delta/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 CK1 delta/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).