Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation

Nat Commun. 2013;4:1790. doi: 10.1038/ncomms2759.

Taro Hitosugi ¹, Lu Zhou, Jun Fan, Shannon Elf, Liang Zhang, Jianxin Xie, Yi Wang, Ting-Lei Gu, Masa Alečković, Gary LeRoy, Yibin Kang, Hee-Bum Kang, Jae-Ho Seo, Changliang Shan, Peng Jin, Weimin Gong, Sagar Lonial, Martha L Arellano, Hanna J Khoury, Georgia Z Chen, Dong M Shin, Fadlo R Khuri, Titus J Boggon, Sumin Kang, Chuan He, Jing Chen

Affiliations

Affiliation

1 Department of Haematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

PMID: 23653202 DOI: 10.1038/ncomms2759

Abstract

How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in Cancer cells remains unclear. We recently reported that the glycolytic Enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate. Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding. Moreover, Y26 phosphorylation of PGAM1 is common in human Cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting Cancer cell proliferation and tumour growth. As PGAM1 is a negative transcriptional target of TP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation.

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