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Cited by 903Protein Kinase Regulation and GTPase SignalingWnt/β-catenin signaling in development and cancerSignaling Pathways in Disease

Inactivation of glycogen synthase kinase-3 β by phosphorylation: new kinase connections in insulin and growth-factor signalling

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Sutherland, C, Leighton, I A, Cohen, P·1993·Biochemical Journal
DOI 10.1042/bj2960015PMC PMC1137648
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Abstract

The beta-isoform of glycogen synthase kinase-3 (GSK3 beta) isolated from rabbit skeletal muscle was inactivated 90-95% following incubation with MgATP and either MAP kinase-activated protein kinase-1 (MAPKAP kinase-1, also termed RSK-2) or p70 S6 kinase (p70S6K), and re-activated with protein phosphatase 2A. MAPKAP kinase-1 and p70S6K phosphorylated the same tryptic peptide on GSK3 beta, and the site of phosphorylation was identified as the serine located nine residues from the N-terminus of the protein. The inhibitory effect of Ser-9 phosphorylation on GSK3 beta activity was observed with three substrates, (inhibitor-2, c-jun and a synthetic peptide), and also with glycogen synthase provided that 0.15 M KCl was added to the assays. The results suggest that Ser-9 phosphorylation underlies the reported inhibition of GSK3 beta by insulin and that GSK3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades.

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  • A well-established mechanism for ERK/Wnt crosstalk involves direct regulation of GSK3β, the master kinase of the β-catenin destruction complex.

    “A well-established mechanism for this crosstalk involves the direct regulation of Glycogen Synthase Kinase 3β (GSK3β), the master kinase of the β-catenin destruction complex [46–51].”

    From PPP1R18-mediated activation of Wnt/β-catenin and EMT is dependent on ERK signaling in clear cell renal cell carcinoma (2026) · cites this paper as [50]

    The indexed Abstract reports that MAP kinase-activated protein kinase-1 (RSK-2) phosphorylated and inactivated GSK3β isolated from rabbit skeletal muscle. That supports kinase-mediated regulation of GSK3β, but our copy does not establish ERK/Wnt crosstalk or identify GSK3β as the master kinase of a β-catenin destruction complex. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Phosphorylation of GSK3β at Ser9 by MAP kinase-activated protein kinase-1 and p70 S6 kinase decreases its activity by 95%.

    “Thus, phosphorylation of GSK3fl by MAP kinaseactivated protein kinase-1 and p70 $6 kinase at Ser 9 decreases its activity by 95% [17].”

    From Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells (1995) · cites this paper as [17]

    The indexed copy gives the 90–95% inactivation, the two kinases, and Ser-9 only in its Abstract, which cannot serve as evidence under this rubric. Searches for the activity reduction and Ser-9 found no Results or other body-text passage; the apparent full-text section contains links rather than the article text. (LLM, conf=0.70)

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Research works printed but not linked: 35

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Authors
Sutherland, C., Leighton, I. A., & Cohen, P.
Affiliations
University of Dundee (GB)
ORCID
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
1993-11-15
Volume
296
Issue
1
Pages
15-19
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj2960015
PMC
PMC1137648
OpenAlex
W1908612571
Cited by
903
References
38
Citations by year
2026: 13 · 2025: 15 · 2024: 22 · 2023: 22 · 2022: 32 · 2021: 28 · 2020: 37 · 2019: 25 · 2018: 26 · 2017: 25 · 2016: 28 · 2015: 31 · 2014: 51 · 2013: 49 · 2012: 39
FWCI
9.67
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
glycogen synthase kinase-3β, p70 S6 kinase, protein phosphatase 2A, glycogen synthase, insulin signaling, growth factor signaling, kinase cascade, skeletal muscle
MeSH terms
Adenosine Triphosphate, Amino Acid Sequence, Animals, Chromatography, Ion Exchange, Enzyme Activation, Insulin, Kinetics, Molecular Sequence Data, Molecular Weight, Muscles, Peptide Fragments, Peptides, Phosphopeptides, Phosphoprotein Phosphatases, Phosphorylation, Rabbits, Signal Transduction, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Glycogen Synthase Kinases, Ribosomal Protein S6 Kinases, 90-kDa, Protein Phosphatase 2

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