title: Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response.
abstract: Protein kinase CK2 is a pleiotropic enzyme, which is implicated in the regulation of numerous biological processes. It seems to regulate the various functions by binding to other proteins and by phosphorylation of many different substrates. Here, we identified the activating transcription factor 4 (ATF4), an essential component of the ER stress signaling, as a new binding partner and a new substrate of CK2 in vitro and in vivo. Bifluorescence complementation analysis (BiFC) revealed that CK2α and ATF4 associate in the nucleus. By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form. We further noticed that an inhibition of CK2 caused an increased transcription of the ATF4 gene. Analyses of the transcription factor activity revealed an impaired activity of the CK2 phosphorylation mutant of ATF4. Thus, we show that (i) ATF4 is a binding partner of CK2α (ii) ATF4 is a substrate of CK2, (iii) the phosphorylation of ATF4 by CK2 influences the stability of ATF4, (iv) the transcription of ATF4 is regulated by CK2 and (v) the transcription factor activity of ATF4 is regulated by the CK2 phosphorylation of ATF4. Thus, CK2 plays an essential role in the regulation of the ER-stress induced signaling pathway.
authors.affiliation: Medizinische Biochemie und Molekularbiologie und Kompetenzzentrum, Molekulare Medizin, Universität des Saarlandes, Gebäude 44, 66424 Homburg, Germany.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Ampofo
authors.forename: Tasja
authors.initials: T
authors.lastname: Sokolowsky
authors.forename: Claudia
authors.initials: C
authors.lastname: Götz
authors.forename: Mathias
authors.initials: M
authors.lastname: Montenarh
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction; D013312:Stress, Physiological; D014158:Transcription, Genetic
chemical_list: C497109:ATF4 protein, human; D051701:Activating Transcription Factor 4; D047390:Casein Kinase II