Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells
Austin, James A. Jenkins, Rosalind E. Austin, Gemma M. Glenn, Mark A. Dunn, Karen Scott, Laura Lucas, Claire Clark, Richard E.
Austin, James A.
Jenkins, Rosalind E.
Austin, Gemma M.
Glenn, Mark A.
Dunn, Karen
Scott, Laura
Lucas, Claire
Clark, Richard E.
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Publication Date
2019-08-15
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Abstract
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5′ AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.
Citation
Austin, J. A., Jenkins, R. E., Austin, G. M., Glenn, M. A.,
Dunn, K., Scott, L., Lucas, C., & Clark, R. E. (2019). Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells. Biochemical Journal, 476(15), 2255-2269. https://doi.org/10.1042/BCJ20190121
Publisher
Portland Press
Journal
Biochemical Journal
Research Unit
DOI
10.1042/BCJ20190121
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PubMed Central ID
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Article
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ISSN
0264-6021
EISSN
1470-8728