Degradation of AMPK by a cancer-specific ubiquitin ligase

Carlos T. Pineda, Saumya Ramanathan, Klementina Fon Tacer, Jenny L. Weon, Malia B. Potts, Yi Hung Ou, Michael A. White, Patrick Ryan Potts

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)715-728
Number of pages14
JournalCell
Volume160
Issue number4
DOIs
StatePublished - Feb 12 2015

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AMP-Activated Protein Kinases
Ligases
Ubiquitin
Degradation
Neoplasms
Cells
Regain
Physiological Stress
Metformin
Ubiquitination
Autophagy
Cell Survival
Screening
Homeostasis
Phosphotransferases
Chemical activation
Mutation
Sensors
Growth
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Pineda, C. T., Ramanathan, S., Fon Tacer, K., Weon, J. L., Potts, M. B., Ou, Y. H., ... Potts, P. R. (2015). Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell, 160(4), 715-728. https://doi.org/10.1016/j.cell.2015.01.034

Degradation of AMPK by a cancer-specific ubiquitin ligase. / Pineda, Carlos T.; Ramanathan, Saumya; Fon Tacer, Klementina; Weon, Jenny L.; Potts, Malia B.; Ou, Yi Hung; White, Michael A.; Potts, Patrick Ryan.

In: Cell, Vol. 160, No. 4, 12.02.2015, p. 715-728.

Research output: Contribution to journalArticle

Pineda, CT, Ramanathan, S, Fon Tacer, K, Weon, JL, Potts, MB, Ou, YH, White, MA & Potts, PR 2015, 'Degradation of AMPK by a cancer-specific ubiquitin ligase', Cell, vol. 160, no. 4, pp. 715-728. https://doi.org/10.1016/j.cell.2015.01.034
Pineda CT, Ramanathan S, Fon Tacer K, Weon JL, Potts MB, Ou YH et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell. 2015 Feb 12;160(4):715-728. https://doi.org/10.1016/j.cell.2015.01.034
Pineda, Carlos T. ; Ramanathan, Saumya ; Fon Tacer, Klementina ; Weon, Jenny L. ; Potts, Malia B. ; Ou, Yi Hung ; White, Michael A. ; Potts, Patrick Ryan. / Degradation of AMPK by a cancer-specific ubiquitin ligase. In: Cell. 2015 ; Vol. 160, No. 4. pp. 715-728.
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