Degradation of AMPK by a Cancer-Specific Ubiquitin Ligase
Open accessAbstract
AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth-restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and are sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The MAGE family of ubiquitin E3 ligases, often called MAGE-RING ligases (MRLs), comprise proteins that serve as substrate-recruitment modules for other RING E3 ligases, adding to and/or altering the substrate specificity of their co-E3 ligases.
“An example of such a family of ligases are the MAGE (melanoma antigen genes) family of ubiquitin E3 ligases, often referred to as the MAGE-RING ligases (MRLs), which comprise proteins that serve as substrate-recruitment modules for other RING E3 ligases156,157, adding to and/or altering the substrate specificity of their co-E3 ligases (reviewed elsewhere155,158).”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [157]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 70 · Cited by 389
- Authors
- Pineda, C. T., Ramanathan, S., Fon Tacer, K., Weon, J. L., Potts, M. B., Ou, Y.-H., White, M. A., & Potts, P. R.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Potts, Patrick Ryan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 4
- Pages
- 715-728
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5629913
- OpenAlex
- W1967199837
- Cited by
- 389
- References
- 70
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 61 · 2023: 37 · 2022: 36 · 2021: 40 · 2020: 34 · 2019: 28 · 2018: 31 · 2017: 29 · 2016: 34 · 2015: 14
- FWCI
- 15.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (GM007062)
- Cancer Prevention and Research Institute of Texas (R1117)
- U.S. Department of Defense (W81XWH-12-1-0446)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- AMPK, MAGE-A3, TRIM28, ubiquitination, protein degradation, cancer metabolism, energy homeostasis, autophagy, mTOR signaling, carcinogenesis
- MeSH terms
- Amino Acid Sequence, Animals, Antigens, Neoplasm, Energy Metabolism, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Proteins, Neoplasms, Testis, Signal Transduction, Sequence Alignment, Mice, AMP-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
