Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1
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We investigated the role of glycogen synthase kinase-3 (GSK-3), which is inactivated by AKT, for its role in the regulation of apoptosis. Upon IL-3 withdrawal, protein levels of MCL-1 decreased but were sustained by pharmacological inhibition of GSK-3, which prevented cytochrome c release and apoptosis. MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1. A phosphorylation-site mutant (MCL-1(S159A)), expressed in IL-3-dependent cells, showed enhanced stability upon IL-3 withdrawal and conferred increased protection from apoptosis compared to wild-type MCL-1. The results demonstrate that the control of MCL-1 stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT.
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GSK3β phosphorylation and subsequent proteasomal degradation of MCL-1 mediate cell death triggered by GSK3β activation.
“Phosphorylation by GSK3 b and subsequently enhanced proteasomal degradation of MCL-1, a pro-survival member of the BCL-2 family of proteins, mediates cell death triggered by GSK3 b activation (Maurer et al., 2006; Wang et al., 2012).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Maurer et al., 2006
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- Authors
- Maurer, U., Charvet, C., Wagman, A. S., Dejardin, E., & Green, D. R.
- Affiliations
- La Jolla Institute for Immunology (US)
- University of Liège (BE)
- Corresponding author
- Maurer, Ulrich
- Green, Douglas R.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 21
- Issue
- 6
- Pages
- 749-760
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2152876030
- Cited by
- 881
- References
- 71
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 16 · 2023: 35 · 2022: 33 · 2021: 41 · 2020: 31 · 2019: 26 · 2018: 39 · 2017: 48 · 2016: 41 · 2015: 48 · 2014: 51 · 2013: 71 · 2012: 62
- FWCI
- 23.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (AI44828, CA-69381, AI40646, GM52735)
- National Cancer Institute (CA 69381, P01CA069381)
- National Institute of General Medical Sciences (GM-52735)
- National Institute of Allergy and Infectious Diseases (R01AI040646, AI40646, AI44828)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- glycogen synthase kinase-3, Mcl-1, mitochondrial outer membrane permeabilization, apoptosis, protein phosphorylation, ubiquitination, protein degradation, IL-3 withdrawal, PI3K signaling, Akt signaling, cytochrome c release
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Cell Survival, Humans, Interleukin-3, Molecular Sequence Data, Neoplasm Proteins, Permeability, Phosphorylation, Time Factors, Transfection, Apoptosis, Sequence Homology, Amino Acid, Proto-Oncogene Proteins c-bcl-2, Phosphatidylinositol 3-Kinases, Glycogen Synthase Kinase 3, Cytochromes c, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, Mitochondrial Membranes, Mice, Myeloid Cell Leukemia Sequence 1 Protein
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