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

Taro Hitosugi, 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 and Jing Chen ()
Additional contact information
Taro Hitosugi: Winship Cancer Institute of Emory, Emory University School of Medicine
Lu Zhou: The University of Chicago
Jun Fan: Winship Cancer Institute of Emory, Emory University School of Medicine
Shannon Elf: Winship Cancer Institute of Emory, Emory University School of Medicine
Liang Zhang: The University of Chicago
Jianxin Xie: Cell Signalling Technology, Inc. (CST)
Yi Wang: Cell Signalling Technology, Inc. (CST)
Ting-Lei Gu: Cell Signalling Technology, Inc. (CST)
Masa Alečković: Washington Road, LTL 255, Princeton University
Gary LeRoy: Washington Road, LTL 255, Princeton University
Yibin Kang: Washington Road, LTL 255, Princeton University
Hee-Bum Kang: Winship Cancer Institute of Emory, Emory University School of Medicine
Jae-Ho Seo: Winship Cancer Institute of Emory, Emory University School of Medicine
Changliang Shan: Winship Cancer Institute of Emory, Emory University School of Medicine
Peng Jin: Emory University School of Medicine
Weimin Gong: Institute of Biophysics, Chinese Academy of Sciences
Sagar Lonial: Winship Cancer Institute of Emory, Emory University School of Medicine
Martha L. Arellano: Winship Cancer Institute of Emory, Emory University School of Medicine
Hanna J. Khoury: Winship Cancer Institute of Emory, Emory University School of Medicine
Georgia Z. Chen: Winship Cancer Institute of Emory, Emory University School of Medicine
Dong M. Shin: Winship Cancer Institute of Emory, Emory University School of Medicine
Fadlo R. Khuri: Winship Cancer Institute of Emory, Emory University School of Medicine
Titus J. Boggon: Yale University School of Medicine
Sumin Kang: Winship Cancer Institute of Emory, Emory University School of Medicine
Chuan He: The University of Chicago
Jing Chen: Winship Cancer Institute of Emory, Emory University School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2759

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