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

• Type of Material: Article
• Authors: Taro Hitosugi, Emory University; Lu Zhou, The University of Chicago; Jun Fan, Emory University; Shannon Elf, Emory University; Liang Zhang, The University of Chicago; Jianxin Xie, Cell Signaling Technology, Inc.; Yi Wang, Cell Signaling Technology, Inc.; Ting-Lei Gu, Cell Signaling Technology, Inc.; Masa Aleckovic, Princeton University; Gary LeRoy, Princeton University; Yibin Kang, Princeton University; HeeBum Kang, Emory University; Jae-Ho Seo, Emory University; Changliang Shan, Emory University; Peng Jin, Emory University; Weimin Gong, Chinese Academy of Sciences; Sagar Lonial, Emory University; Martha Arellano, Emory University; H Jean Khoury, Emory University; Georgia Chen, Emory University; Dong M Shin, Emory University; Fadlo Khuri, Emory University; Titus J. Boggon, Yale University; Sumin Kang, Emory University; Chuan He, The University of Chicago; Jing Chen, Emory University
• Language: English
• Date: 2013
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://www.nature.com/ncomms/journal/v4/n4/full/ncomms2759.html
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 4
• Start Page: 1790
• End Page: 1790
• Grant/Funding Information: This work was supported in part by NIH grants CA120272 (J.C.), CA140515 (J.C.), GM071440 (C.H.), DoD grant W81XWH-12-1-0217 (J.C.), the Pharmacological Sciences Training Grant T32 GM008602 (S.E.) and the National Natural Science Funds of China No. 20902013 (L.Zhou).
• Research Categories: Biology, Molecular; Health Sciences, Oncology; Biology, Genetics

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 (3-PG) and product 2-phosphoglycerate (2-PG). 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-PG binding. Moreover, Y26-phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-PG and 2-PG levels, promoting cancer cell proliferation and tumour growth. Since PGAM1 as a negative transcription target of TP53 is commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying PGAM1 upregulation.