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Correspondence and requests of materials should be addressed to C.H. (jchen@emory.edu)

The first two authors contributed equally to this work.

Author contributions T.H., L.Zhou, S.L., F.R.K., S.K., C.H. and J.C. designed this study. T.H. and J.F. performed experiments with help of S.E., H.-B.K., J.-H.S., and C.S. L.Zhou, L.Zhang and H.C. performed the crystallography experiments and data analysis with help of P.J and W.G. J.X., Y.W. and T.-L.G. performed the phospho-proteomics studies and generated the specific phospho-PGAM1 (pY26) antibody. M.A., G.L. and Y.K. performed mass spectrometry analysis. S.E., M.L.A, H.J.K., G.Z.C. and D.M.S. performed experiments to detect Y26 phosphorylation in human patient tissue samples. T.J.B. performed structural analysis. T.H., L.Zhou, S.K., C.H. and J.C. wrote the manuscript. All authors read and approved the final manuscript.

Acknowledgments: T.H. is a Fellow Scholar of the American Society of Haematology. J.X., Y.W. and T.-L.G. are employees of Cell Signaling Technology, Inc. G.Z.C., S.M.S., F.R.K., S.K. and J.C. are Georgia Cancer Coalition Distinguished Cancer Scholars. S. K. is a Robbins Scholar. S.K. and J.C. are American Cancer Society Basic Research Scholars. J.C. is a Scholar of the Leukaemia and Lymphoma Society.

Conflict of Interest The authors have declared that no conflict of interest exists.

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Research Funding:

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).

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

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Journal Title:

Nature Communications

Volume:

Volume 4

Publisher:

, Pages 1790-1790

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Article | Final Publisher PDF

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.

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