The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation

Nina Gustafsson Sheppard, Lisa Jarl, Diana Mahadessian, Laura Strittmatter, Angelika Schmidt, Nikhil Madhusudan, Jesper Tegnér, Emma K. Lundberg, Anna Asplund, Mohit Jain, Roland Nilsson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Folate metabolism is central to cell proliferation and a target of commonly used cancer chemotherapeutics. In particular, the mitochondrial folate-coupled metabolism is thought to be important for proliferating cancer cells. The enzyme MTHFD2 in this pathway is highly expressed in human tumors and broadly required for survival of cancer cells. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in cancer cell biology. We here report that MTHFD2 is co-expressed with two distinct gene sets, representing amino acid metabolism and cell proliferation, respectively. Consistent with a role for MTHFD2 in cell proliferation, MTHFD2 expression was repressed in cells rendered quiescent by deprivation of growth signals (serum) and rapidly re-induced by serum stimulation. Overexpression of MTHFD2 alone was sufficient to promote cell proliferation independent of its dehydrogenase activity, even during growth restriction. In addition to its known mitochondrial localization, we found MTHFD2 to have a nuclear localization and co-localize with DNA replication sites. These findings suggest a previously unknown role for MTHFD2 in cancer cell proliferation, adding to its known function in mitochondrial folate metabolism.

Original languageEnglish (US)
Article number15029
JournalScientific Reports
StatePublished - Oct 13 2015
Externally publishedYes

Bibliographical note

Funding Information:
The authors would like to thank Vamsi K Mootha for providing overexpression constructs for MTHFD2 and MTHFD2-dead. This research was supported by the Swedish Society for Medical Research and VR Medicine grant no. B0305901 (NGS), Marie Curie Intra European Fellowship within the 7th European Community Framework Programme (to AS.), VR Medicine grant no. B0326401 (JT, AS), Stockholm County Council no. 01626-2009 (JT, AS), Mary Kay Foundation (MJ), the Strategic Programme in Cancer Research at Karolinska Institutet and Stiftelsen for Strategisk Forskning grant no. ICA10-0023 (RN), Jeanssons Stiftelser grant no. JS2012-0137 (LJ) and Cancerfonden grant no. CAN2013/822.

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