Regulation of calcium/calmodulin-dependent kinase IV by O-GlcNAc modification

Wagner B. Bias, Win D. Cheung, Zihao Wang, Gerald Warren Hart

Research output: Contribution to journalArticlepeer-review

97 Scopus citations


Similar to phosphorylation, GlcNAcylation (the addition of O-GlcNAc to Ser(Thr) residues on polypeptides) is an abundant, dynamic, and inducible post-translational modification. Glc-NAcylated proteins are crucial in regulating virtually all cellular processes, including signaling, cell cycle, and transcription. Here we show that calcium/ calmodulin-dependent kinase IV (CaMKIV) is highly GlcNAcylated in vivo. In addition, we show that upon activation of HEK293 cells, hemagglutinin-tagged CaMKIV GlcNAcylation rapidly decreases, in a manner directly opposing its phosphorylation at Thr-200. Correspondingly, there is an increase in CaMKIV interaction with O-GlcNAcase during CaMKIV activation. Furthermore, we identify at least five sites of GlcNAcylation on CaMKIV. Using site-directed mutagenesis, we determine that the GlcNAcylation sites located in the active site of CaMKIV can modulate its phosphorylation at Thr-200 and its activity toward cAMP-response element-binding transcription factor. Our results strongly indicate that the O-GlcNAc modification participates in the regulation of CaMKIV activation and function, possibly coordinating nutritional signals with the immune and nervous systems. This is the first example of an O-GlcNAc/phosphate cycle involving O-GlcNAc transferase/kinase cross-talk.

Original languageEnglish (US)
Pages (from-to)21327-21337
Number of pages11
JournalJournal of Biological Chemistry
Issue number32
StatePublished - Aug 7 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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