A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).
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).
Zhao
Bin
B
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093-0815, USA.
Li
Li
L
Tumaneng
Karen
K
Wang
Cun-Yu
CY
Guan
Kun-Liang
KL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D047389:Casein Kinase I / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors; D054875:Ubiquitination; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D012694:Serine; D044843:SKP Cullin F-Box Protein Ligases; C092745:LATS1 protein, human; D047389:Casein Kinase I; D017346:Protein Serine-Threonine Kinases