The O-GlcNAc Modification on Kinases

Abstract

O-Linked N-acetyl glucosamine (O-GlcNAc) is a protein modification found on thousands of nuclear, cytosolic, and mitochondrial proteins. Many O-GlcNAc sites occur in close proximity to protein sites that are likewise modified by phosphorylation. While several studies have uncovered crosstalk between these two signaling modifications on individual proteins and pathways, an understanding of the role of O-GlcNAc in regulating kinases, the enzymes that install the phosphate modification, is still emerging. Here we review recent methods to profile the O-GlcNAc modification on a global scale that have revealed over 100 kinases as modified by O-GlcNAc, and highlight existing studies about regulation of these kinases by O-GlcNAc. Continuing efforts to profile the O-GlcNAc proteome and understand the role of O-GlcNAc on kinases will reveal new mechanisms of regulation and potential avenues for manipulation of the signaling mechanisms at the intersection of O-GlcNAc and phosphorylation.

O‑GlcNAcylation contributes to intermittent hypoxia‑associated vascular dysfunction via modulation of MAPKs but not CaMKII pathways

“…These findings supported the present study hypothesis that MAPK pathway activation contributed to CIH-related vascular dysfunction. However, despite evidence that IH could affect CaMKII activity ( 44 , 45 ) and a similar finding showing an increased phosphorylated modification of CaMKII by increased O-GlcNAc levels ( 11 , 22 ), CaMKII blockade did not alter vascular contractile responses to PE or Ang II in any of the groups studied, indicating the lack of CaMKII involvement in the regulation of IH-related vasoconstriction.…”

“…A number of kinases or phosphatases can be modified by O-GlcNAcylation, including the CaMK, CK1, tyrosine kinases (TK) and Sterile (STE) kinase families ( 11 ). It was further observed in the present study that p38 MAPK and ERK1/2 were phosphorylated in response to enhanced O-GlcNAc levels, whereas reducing O-GlcNAcylation tended to decrease the phosphorylation of these kinases, which was consistent with earlier research showing that O-GlcNAc levels could affect MAPK phosphorylation dynamics.…”

“…These findings were consistent with the results of vascular contractile responses. The reason for these findings may have been the differences between the target protein substrates of OGA and those of OGT ( 10 , 11 , 18 ).…”

“…O-linked-β-N-acetylglucosamine (O-GlcNAc) modifications on serine/threonine (Ser/Thr) residues of proteins, known as O-GlcNAcylation, are a critical regulatory post-translational modification (PTM), analogous to phosphorylation, that can induce functional changes in numerous target proteins, including protein kinases, phosphatases, cellular signaling proteins and transcriptional factors ( 10 , 11 ). O-GlcNAcylation is controlled by two conserved enzymes, namely O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA).…”

“…OGA and OGT often occur in the same protein complexes as kinases and phosphatases, suggesting that a protein can quickly cycle between being phosphorylated and O-GlcNAcylated ( 10 , 18 ). An increasing number of kinases have been found to be O-GlcNAcylated, resulting in conformational changes that promote downstream functional effects ( 11 ). The important regulatory role of phosphorylation in a subset of proteins associated with transcriptional factor activation, signaling pathways and neurotransmitter synthesis has been identified in OSA-related autonomic abnormalities ( 5 , 8 , 19 ).…”