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Cited by 54Redox biology and oxidative stressProtein Kinase Regulation and GTPase SignalingWnt/β-catenin signaling in development and cancer

Protein S -Nitrosylation Controls Glycogen Synthase Kinase 3β Function Independent of Its Phosphorylation State

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Wang, Sheng-Bing, Venkatraman, Vidya, Crowgey, Erin L., Liu, Ting, Fu, Zongming, Holewinski, Ronald, Ranek, Mark, Kass, David A. +2 more·2018·Circulation Research
DOI 10.1161/circresaha.118.312789PMC PMC6047766
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Abstract

Rationale: GSK-3β (glycogen synthase kinase 3β) is a multifunctional and constitutively active kinase known to regulate a myriad of cellular processes. The primary mechanism to regulate its function is through phosphorylation-dependent inhibition at serine-9 residue. Emerging evidence indicates that there may be alternative mechanisms that control GSK-3β for certain functions. Objectives: Here, we sought to understand the role of protein S -nitrosylation (SNO) on the function of GSK-3β. SNO-dependent modulation of the localization of GSK-3β and its ability to phosphorylate downstream targets was investigated in vitro, and the network of proteins differentially impacted by phospho- or SNO-dependent GSK-3β regulation and in vivo SNO modification of key signaling kinases during the development of heart failure was also studied. Methods and Results: We found that GSK-3β undergoes site-specific SNO both in vitro, in HEK293 cells, H9C2 myoblasts, and primary neonatal rat ventricular myocytes, as well as in vivo, in hearts from an animal model of heart failure and sudden cardiac death. S -nitrosylation of GSK-3β significantly inhibits its kinase activity independent of the canonical phospho-inhibition pathway. S -nitrosylation of GSK-3β promotes its nuclear translocation and access to novel downstream phosphosubstrates which are enriched for a novel amino acid consensus sequence motif. Quantitative phosphoproteomics pathway analysis reveals that nuclear GSK-3β plays a central role in cell cycle control, RNA splicing, and DNA damage response. Conclusions: The results indicate that SNO has a differential effect on the location and activity of GSK-3β in the cytoplasm versus the nucleus. SNO modification of GSK-3β occurs in vivo and could contribute to the pathobiology of heart failure and sudden cardiac death.

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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 [51]

    The Introduction (page unavailable) says ERK phosphorylates GSK3β and that GSK3β regulates Wnt signaling and β-catenin degradation. It does not establish that ERK’s regulation of GSK3β mediates ERK/Wnt crosstalk; it also says β-catenin degradation is an exception to phosphorylation-dependent inhibition of GSK3β. (LLM, conf=0.86)

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Authors
Wang, S.-B., Venkatraman, V., Crowgey, E. L., Liu, T., Fu, Z., Holewinski, R., Ranek, M., Kass, D. A., O’Rourke, B., & Van Eyk, J. E.
Affiliations
  • From the Department of Medicine (S.-B.W., V.V., T.L., R.H., M.R., D.A.K., B.O'R., J.E.V.E.)
  • Cedars-Sinai Medical Center (US)
  • Alfred I. duPont Hospital for Children (US)
  • Department of Pediatrics (Z.F.)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-05-25
Volume
122
Issue
11
Pages
1517-1531
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.118.312789
PMC
PMC6047766
OpenAlex
W2791474607
Cited by
54
References
61
Citations by year
2026: 7 · 2025: 7 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 4
FWCI
2.13
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Johns Hopkins University
  • Cedars-Sinai Medical Center
  • National Institutes of Health (n01hv28180-13-0-0)
  • National Heart, Lung, and Blood Institute (NHLBI-HV-10-05, HV-10-05_, P01HL077180, N01 HV028180, R01HL137259, R35HL135827, P01 HL77189-01, P01HL77189, T32HL007227)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • 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
Keywords
S-nitrosylation, glycogen synthase kinase-3β, kinase inhibition, nuclear translocation, phosphoproteomics, heart failure, sudden cardiac death, cell cycle regulation, RNA splicing, DNA damage response, neonatal rat ventricular myocytes, H9c2 myoblasts, HEK293 cells
MeSH terms
Glycogen Synthase Kinase 3 beta, Animals, Cell Nucleus, Cytoplasm, Disease Models, Animal, Guinea Pigs, Heart Failure, Nitric Oxide, Phosphorylation, Signal Transduction, Death, Sudden, Cardiac, Protein S, Myocytes, Cardiac

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