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; Jing Chen

doi:10.1038/ncomms2759

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. ChenDong M. Shin, Fadlo R. Khuri, Titus J. Boggon, Sumin Kang, Chuan He, Jing Chen

Oncology

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

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.

Original language	English (US)
Article number	1790
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms2759
State	Published - 2013

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms2759

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Hitosugi, T., Zhou, L., Fan, J., Elf, S., Zhang, L., Xie, J., Wang, Y., Gu, T. L., Alečković, M., Leroy, G., Kang, Y., Kang, H. B., Seo, J. H., Shan, C., Jin, P., Gong, W., Lonial, S., Arellano, M. L., Khoury, H. J., ... Chen, J. (2013). Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nature communications, 4, Article 1790. https://doi.org/10.1038/ncomms2759

Hitosugi, T, Zhou, L, Fan, J, Elf, S, Zhang, L, Xie, J, Wang, Y, Gu, TL, Alečković, M, Leroy, G, Kang, Y, Kang, HB, Seo, JH, Shan, C, Jin, P, Gong, W, Lonial, S, Arellano, ML, Khoury, HJ, Chen, GZ, Shin, DM, Khuri, FR, Boggon, TJ, Kang, S, He, C & Chen, J 2013, 'Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation', Nature communications, vol. 4, 1790. https://doi.org/10.1038/ncomms2759

@article{c2f530fac1814c96820c172552280ffa,

title = "Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation",

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.",

author = "Taro Hitosugi and Lu Zhou and Jun Fan and Shannon Elf and Liang Zhang and Jianxin Xie and Yi Wang and Gu, {Ting Lei} and Masa Ale{\v c}kovi{\'c} and Gary Leroy and Yibin Kang and Kang, {Hee Bum} and Seo, {Jae Ho} and Changliang Shan and Peng Jin and Weimin Gong and Sagar Lonial and Arellano, {Martha L.} and Khoury, {Hanna J.} and Chen, {Georgia Z.} and Shin, {Dong M.} and Khuri, {Fadlo R.} and Boggon, {Titus J.} and Sumin Kang and Chuan He and Jing Chen",

note = "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). 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. We thank Dr. Benjamin A. Garcia for providing mass spectrometry equipment and technical assistance.",

year = "2013",

doi = "10.1038/ncomms2759",

language = "English (US)",

volume = "4",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation

AU - Hitosugi, Taro

AU - Zhou, Lu

AU - Fan, Jun

AU - Elf, Shannon

AU - Zhang, Liang

AU - Xie, Jianxin

AU - Wang, Yi

AU - Gu, Ting Lei

AU - Alečković, Masa

AU - Leroy, Gary

AU - Kang, Yibin

AU - Kang, Hee Bum

AU - Seo, Jae Ho

AU - Shan, Changliang

AU - Jin, Peng

AU - Gong, Weimin

AU - Lonial, Sagar

AU - Arellano, Martha L.

AU - Khoury, Hanna J.

AU - Chen, Georgia Z.

AU - Shin, Dong M.

AU - Khuri, Fadlo R.

AU - Boggon, Titus J.

AU - Kang, Sumin

AU - He, Chuan

AU - Chen, Jing

N1 - 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). 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. We thank Dr. Benjamin A. Garcia for providing mass spectrometry equipment and technical assistance.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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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U2 - 10.1038/ncomms2759

DO - 10.1038/ncomms2759

M3 - Article

C2 - 23653202

AN - SCOPUS:84877781067

SN - 2041-1723

VL - 4

JO - Nature communications

JF - Nature communications

M1 - 1790

ER -

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

Abstract

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