Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 337 (6097): 975-980

Copyright © 2012 by the American Association for the Advancement of Science

Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

Wen Yi,1,2 Peter M. Clark,1,2 Daniel E. Mason,3 Marie C. Keenan,4 Collin Hill,4 William A. Goddard, III,5 Eric C. Peters,3 Edward M. Driggers,4 Linda C. Hsieh-Wilson1,2,*

Abstract: Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention.

1 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
2 Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
3 Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
4 Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
5 Materials and Process Simulation Center, California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, Pasadena, CA 91125, USA.

* To whom correspondence should be addressed. E-mail: lhw{at}

HCF-1 Is Cleaved in the Active Site of O-GlcNAc Transferase.
M. B. Lazarus, J. Jiang, V. Kapuria, T. Bhuiyan, J. Janetzko, W. F. Zandberg, D. J. Vocadlo, W. Herr, and S. Walker (2013)
Science 342, 1235-1239
   Abstract »    Full Text »    PDF »
Mouse Embryonic Stem Cells Established in Physiological-Glucose Media Express the High KM Glut2 Glucose Transporter Expressed by Normal Embryos.
J. H. Jung, X. D. Wang, and M. R. Loeken (2013)
Stem Cells Trans Med 2, 929-934
   Abstract »    Full Text »    PDF »
Twenty-fifth Annual Pezcoller Symposium: Metabolism and Tumorigenesis.
W. Kaelin, D. Livingston, M. Loda, K. Vousden, and E. Mihich (2013)
Cancer Res. 73, 6124-6127
   Abstract »    Full Text »    PDF »
O-Linked N-Acetylglucosamine Cycling Regulates Mitotic Spindle Organization.
E. P. Tan, S. Caro, A. Potnis, C. Lanza, and C. Slawson (2013)
J. Biol. Chem. 288, 27085-27099
   Abstract »    Full Text »    PDF »
Engineering the Pattern of Protein Glycosylation Modulates the Thermostability of a GH11 Xylanase.
R. Fonseca-Maldonado, D. S. Vieira, J. S. Alponti, E. Bonneil, P. Thibault, and R. J. Ward (2013)
J. Biol. Chem. 288, 25522-25534
   Abstract »    Full Text »    PDF »
Functional Lysine Modification by an Intrinsically Reactive Primary Glycolytic Metabolite.
R. E. Moellering and B. F. Cravatt (2013)
Science 341, 549-553
   Abstract »    Full Text »    PDF »
AMPK: A Contextual Oncogene or Tumor Suppressor?.
J. Liang and G. B. Mills (2013)
Cancer Res. 73, 2929-2935
   Abstract »    Full Text »    PDF »
Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma.
F. Guillaumond, J. Leca, O. Olivares, M.-N. Lavaut, N. Vidal, P. Berthezene, N. J. Dusetti, C. Loncle, E. Calvo, O. Turrini, et al. (2013)
PNAS 110, 3919-3924
   Abstract »    Full Text »    PDF »
Targeting of Several Glycolytic Enzymes Using RNA Interference Reveals Aldolase Affects Cancer Cell Proliferation through a Non-glycolytic Mechanism.
C. R. Lew and D. R. Tolan (2012)
J. Biol. Chem. 287, 42554-42563
   Abstract »    Full Text »    PDF »
Glycosylation to Adapt to Stress.
K. R. Mattaini and M. G. Vander Heiden (2012)
Science 337, 925-926
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882