title: Expression and regulation of glycogen synthase kinase 3 in human neutrophils.
abstract: Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase involved in the regulation of cellular processes ranging from glycogen metabolism to cell cycle regulation. Its two known isoforms, α and β, are differentially expressed in tissues throughout the body and exert distinct but often overlapping functions. GSK-3 is typically active in resting cells, inhibition by phosphorylation of Ser21 (GSK-3α) or Ser9 (GSK-3β) being the most common regulatory mechanism. GSK-3 activity has been linked recently with immune system function, yet little is known about the role of this enzyme in neutrophils, the most abundant leukocyte type. In the present study, we examined GSK-3 expression and regulation in human neutrophils. GSK-3α was found to be the predominant isoform, it was constitutively expressed and cell stimulation with different agonists did not alter its expression. Stimulation by fMLP, LPS, GM-CSF, Fcγ receptor engagement, or adenosine A2A receptor engagement all resulted in phosphorylation of Ser21. The use of metabolic inhibitors revealed that combinations of Src kinase, PKC, PI3K/AKT, ERK/RSK and PKA signaling pathways could mediate phosphorylation, depending on the agonist. Neither PLC nor p38 were involved. We conclude that GSK-3α is the main isoform expressed in neutrophils and that many different pathways can converge to inhibit GSK-3α activity via Ser21-phosphorylation. GSK-3α thus might be a hub of cellular regulation.
authors.affiliation: Centre de Recherche du CHU de Québec and Faculty of Medicine, Université Laval, Quebec City, Canada.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Giambelluca
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cloutier
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Rollet-Labelle
authors.forename: Eric
authors.initials: E
authors.lastname: Boilard
authors.forename: Marc
authors.initials: M
authors.lastname: Pouliot
mesh_terms: D015153:Blotting, Western; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology*; D010766:Phosphorylation; D013997:Time Factors
chemical_list: D007527:Isoenzymes; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: Agonists; Glycogen synthase kinase 3; Neutrophils; Phosphorylation; Signal transduction