Protein Interaction and Functional Data Indicate MTHFD2 Involvement in RNA Processing and Translation

Overview

Journal Cancer Metab

Publisher Biomed Central

Specialty Oncology

Date 2018 Oct 3

PMID 30275950

Citations 22

Authors

Costas Koufaris

Roland Nilsson

Affiliations

Soon will be listed here.

Abstract

Background: The folate-coupled metabolic enzyme MTHFD2 is overexpressed in many tumor types and required for cancer cell proliferation, and is therefore of interest as a potential cancer therapeutic target. However, recent evidence suggests that MTHFD2 has a non-enzymatic function which may underlie the dependence of cancer cells on this protein. Understanding this non-enzymatic function is important for optimal targeting of MTHFD2 in cancer.

Methods: To identify potential non-enzymatic functions of MTHFD2, we defined its interacting proteins using co-immunoprecipitation and mass spectrometry and integrated this information with large-scale co-expression analysis, protein dynamics, and gene expression response to MTHFD2 knockdown.

Results: We found that MTHFD2 physically interacts with a set of nuclear proteins involved in RNA metabolism and translation, including components of the small ribosomal subunit and multiple members of the RNA-processing hnRNP family. Interacting proteins were also in general co-expressed with MTHFD2 in experiments that stimulate or repress proliferation, suggesting a close functional relationship. Also, unlike other folate one-carbon enzymes, the MTHFD2 protein has a short half-life and responds rapidly to serum. Finally, shRNA against MTHFD2 depletes several of its interactors and yields an overall transcriptional response similar to targeted inhibition of certain ribosomal subunits.

Conclusions: Taken together, our findings suggest a novel function of MTHFD2 in RNA metabolism and translation.

Citing Articles

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Nuclear localization of MTHFD2 is required for correct mitosis progression.

Pardo-Lorente N, Gkanogiannis A, Cozzuto L, Ganez Zapater A, Espinar L, Ghose R Nat Commun. 2024; 15(1):9529.

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Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L.

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The one-carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation.

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SNHG3/hsa-miR-455-5p Axis-mediated High Expression of MTHFD2 Correlates with Tumor Immune Infiltration and Endometrial Carcinoma Progression.

Wu S, Cai W, Li Y, Tan W, Yuan Y, Zhou Z Int J Med Sci. 2023; 20(8):1097-1113.

PMID: 37484807 PMC: 10357439. DOI: 10.7150/ijms.81962.

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