Wnt5a controls Notch1 signaling through CaMKII-mediated degradation of the SMRT corepressor protein.
Serine-threonine Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is the key component in noncanonical Wnt5a signaling and has been shown to regulate its signaling. In this study, we found that CaMKII induced by Wnt5a remarkably reduced the protein stability of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), a co-repressor of Notch signaling, through proteasomal degradation. Wnt5a was found to enhance Notch1 intracellular domain (Notch1-IC) transcription activity, which could be inhibited by treatment with KN93, a CaMKII inhibitor. The kinase activity of CaMKII was essential for the activation of Notch signaling. We also determined that CaMKII could enhance the association between Notch1-IC and RBP-Jk. Furthermore, the physical association between RBP-Jk and SMRT was substantially suppressed by CaMKII. We demonstrated that CaMKII directly bound and phosphorylated SMRT at Ser-1407, thereby facilitating SMRT translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. These results suggest that CaMKII down-regulated the protein stability of SMRT through proteasomal degradation.
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Eun-Jung
EJ
Ann
Hwa-Young
HY
Kim
Mi-Sun
MS
Seo
Jung-Soon
JS
Mo
Mi-Yeon
MY
Kim
Ji-Hye
JH
Yoon
Ji-Seon
JS
Ahn
Hee-Sae
HS
Park
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D015536:Down-Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1; D015533:Transcriptional Activation; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein
D051792:Basic Helix-Loop-Helix Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008156:Luciferases; D056985:Nuclear Receptor Co-Repressor 2; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C539130:NCOR2 protein, human; C497761:NOTCH1 protein, human; C085389:WNT5A protein, human; C077478:HES5 protein, human; C078493:HES1 protein, human