Homeodomain-interacting protein kinase-2 mediates CtBP phosphorylation and degradation in UV-triggered apoptosis.
Homeodomain-interacting protein kinase-2 (HIPK2) is a serine/threonine kinase involved in transcriptional regulation and apoptosis. The transcriptional corepressor CtBP (carboxyl-terminal binding protein) also plays a fundamental role in these processes. Our previous studies indicate that HIPK2 participates in a pathway of UV-triggered CtBP clearance that results in cell death. HIPK2 phosphorylates CtBP at Ser-422 in vitro. We developed a Ser-422 phospho-specific antibody to demonstrate that CtBP is phosphorylated on this residue in response to UV irradiation. HIPK2 knock-down blocked the UV-induced Ser-422 phosphorylation and degradation. The proteasomal inhibitor MG-132 treatment increased levels of ubiquitinated CtBP, which was induced by UV. Interference with HIPK2 function via the kinase-dead mutant decreased CtBP ubiquitination. Furthermore, a phosphopeptide spanning Ser-422 blocked UV-triggered CtBP degradation, confirming that Ser-422 phosphorylation marks CtBP for clearance. Consequently, interference with HIPK2 action in H1299 cells rescued UV-triggered apoptosis.
Zhang
Qinghong
Q
Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Nottke
Amanda
A
Goodman
Richard H
RH
D000429:Alcohol Oxidoreductases; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011817:Rabbits; D012694:Serine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007976:Leupeptins; D010750:Phosphoproteins; D025801:Ubiquitin; D012694:Serine; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde