Inhibition of Glycogen Synthase Kinase 3 Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle

Nikoulina, Svetlana E.; Ciaraldi, Theodore P.; Mudaliar, Sunder; Carter, Leslie; Johnson, Kirk W.; Henry, Robert R.

doi:10.2337/diabetes.51.7.2190

Cited by 174 publications

(153 citation statements)

References 60 publications

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“…It was first demonstrated that sites 3a and 3b were phosphorylated by the protein kinase GSK-3 (11)(12)(13). Studies with cells and with animals have also shown that known inhibitors of GSK-3 can affect glycogen synthesis (26,27). However, more recent studies indicated that alternative pathway(s) for the phosphorylation of these sites in glycogen synthase may operate (10,18).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Ser640 in Muscle Glycogen Synthase by DYRK Family Protein Kinases

Skurat

Dietrich

2004

Journal of Biological Chemistry

104

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Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation. Glycogen synthase kinase-3 (GSK-3) phosphorylates four serine residues in the COOH terminus of glycogen synthase. Phosphorylation of one of these residues, Ser 640 (site 3a), causes strong inactivation of glycogen synthase. In previous work, we demonstrated in cell models that site 3a can be phosphorylated by an as yet unidentified protein kinase (3a-kinase) distinct from GSK-3. In the present study, we purified the 3a-kinase from rabbit skeletal muscle and identified one constituent polypeptide as HAN11, a WD40 domain protein with unknown function. Another polypeptide was identified as DYRK1A, a member of the dual-specificity tyrosine phosphorylated and regulated protein kinase (DYRK) family. Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. Co-expression of DYRK1A, DYRK1B, or DYRK2 with a series of glycogen synthase mutants with Ser/Ala substitutions at the phosphorylation sites in COS cells revealed that protein kinases cause phosphorylation of site 3a in glycogen synthase. To confirm that DYRKs directly phosphorylate glycogen synthase, recombinant DYRK1A, DYRK2, and glycogen synthase were produced in bacterial cells. In the presence of Mg-ATP, both DYRKs inactivated glycogen synthase by more than 10-fold. The inactivation correlated with phosphorylation of site 3a in glycogen synthase. These results indicate that protein kinase(s) from the DYRK family may be involved in a new mechanism for the regulation of glycogen synthesis.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Ser640 in Muscle Glycogen Synthase by DYRK Family Protein Kinases

Skurat

Dietrich

2004

Journal of Biological Chemistry

104

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“…In one of the few reports, Nikoulina et al (37) found that inhibition of GSK-3 for 4 days increased both basal and insulin-stimulated glucose uptake in skeletal muscle without changing expression of either GLUT1 or GLUT4. Similarly, Bentley et al (4) showed that IL-3 stimulated translocation of GLUT1 to the cell surface of mast cells, and Wieman et al (42) found that this IL-3 effect on Fig.…”

Section: Discussionmentioning

confidence: 99%

“…GSK-3 is known to function downstream of phosphatidylinositol 3-kinase (PI3K) and Akt (41). There is a paucity of reports about regulation of GLUT1 mediated glucose uptake by GSK-3, and the few studies that have been performed have produced different findings in different cell systems (37,42).…”

mentioning

confidence: 99%

A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression

Buller

Loberg

Fan

et al. 2008

American Journal of Physiology-Cell Physiology

204

167

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“…5A). We surmised that this protein could be Gsk-3␤ on the basis of the molecular weight and its known involvement in the regulation of glucose metabolism (44). Phosphorylation of Gsk-3␤ Ser-9, the Akt-dependent phosphorylation site in Gsk-3␤, increased significantly in Irs-1 Ϫ/Ϫ /Irs-2 Ϫ/Ϫ cells expressing WT Irs-2 relative to vector controls, and this increase was not observed in the same cells expressing Irs-2 Y5F (Fig.…”

Section: Irs-2mentioning

confidence: 99%

Insulin Receptor Substrate 2-mediated Phosphatidylinositol 3-kinase Signaling Selectively Inhibits Glycogen Synthase Kinase 3β to Regulate Aerobic Glycolysis

Landis

Shaw

2014

Journal of Biological Chemistry

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Background: Insulin receptor substrate 2 (Irs-2)-mediated signaling by the insulin and insulin-like growth factor 1 receptors regulates metabolism. Results: Direct activation of PI3K by Irs-2 inhibits glycogen synthase kinase 3␤ (Gsk-3␤) to stimulate glucose uptake and aerobic glycolysis. Conclusion: Irs-1 and Irs-2 regulate distinct subsets of Akt effectors. Significance: The Irs-2-mediated PI3K signaling pathway could be targeted to inhibit tumor metabolism.

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Inhibition of Glycogen Synthase Kinase 3 Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle

Abstract: Glycogen synthase kinase (GSK)-

Cited by 174 publications

References 60 publications

Phosphorylation of Ser640 in Muscle Glycogen Synthase by DYRK Family Protein Kinases

Phosphorylation of Ser640 in Muscle Glycogen Synthase by DYRK Family Protein Kinases

A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression

Insulin Receptor Substrate 2-mediated Phosphatidylinositol 3-kinase Signaling Selectively Inhibits Glycogen Synthase Kinase 3β to Regulate Aerobic Glycolysis

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