Journal article
Carboxy-Methylation of the Catalytic Subunit of Protein Phosphatase 2A (PP2Ac) Integrates Methionine Availability with Methionine Addicted Cancer Cell Proliferation
Biomolecules (Basel, Switzerland), Vol.15(9), p.1210
08/22/2025
DOI: 10.3390/biom15091210
PMID: 41008516
Abstract
Cancer cells exhibit a well-documented, yet poorly understood, dependence on exogenous methionine, despite retaining the capacity to convert homocysteine to methionine. In contrast, non-tumorigenic cells can proliferate when methionine is replaced by homocysteine. To investigate the mechanistic basis of this methionine dependence, we examined how methionine metabolism impacts cancer cell proliferation. We identified carboxy-methylation of the catalytic subunit of Protein Phosphatase 2A (PP2A) as a critical node linking methionine availability to proliferation. PP2A methylation was found to be highly sensitive to intracellular S-adenosylmethionine (SAM) levels, with reduced methylation correlating with impaired proliferation under methionine restriction. Overexpression of Protein Phosphatase Methylesterase-1 (PME-1), which demethylates PP2A, or expression of a Leu309-deleted PP2A mutant that mimics the demethylated form, was sufficient to reduce proliferation even in methionine-independent cells. These findings support a model in which methionine limitation lowers SAM availability, thereby decreasing PP2A methylation and impairing cell proliferation. Our study reveals a mechanistic link between methionine metabolism and cell proliferation and suggests that PP2A methylation plays a key role in the unique methionine dependence of cancer cells.
Details
- Title: Subtitle
- Carboxy-Methylation of the Catalytic Subunit of Protein Phosphatase 2A (PP2Ac) Integrates Methionine Availability with Methionine Addicted Cancer Cell Proliferation
- Creators
- Anna Andronicos - University of California, IrvineKiku C. Yoneda - University of California, IrvineDa-Wei Lin - University of California, IrvineFiona V. Law - University of California, IrvineHosung Bae - University of California, IrvineAli Basirattalab - University of Southern CaliforniaNicholas A. Graham - University of Southern CaliforniaCholsoon Jang - University of California, IrvinePeter Kaiser - University of California, Irvine
- Resource Type
- Journal article
- Publication Details
- Biomolecules (Basel, Switzerland), Vol.15(9), p.1210
- DOI
- 10.3390/biom15091210
- PMID
- 41008516
- NLM abbreviation
- Biomolecules
- ISSN
- 2218-273X
- eISSN
- 2218-273X
- Publisher
- Mdpi
- Number of pages
- 26
- Grant note
- NCI T32CA009054; R21 GM144910; R01-AA029124 / Chao Family Comprehensive Cancer Center NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 08/22/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217029202771
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