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.

Subscribe

Logo for

Genes & Dev. 25 (16): 1716-1733

Copyright © 2011 by Cold Spring Harbor Laboratory Press.

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Alexandra R. Grassian1,4, Christian M. Metallo2,3,4, Jonathan L. Coloff1, Gregory Stephanopoulos2,, and Joan S. Brugge1,5

1 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
2 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Abstract: Loss of extracellular matrix (ECM) attachment leads to metabolic impairments that limit cellular energy production. Characterization of the metabolic alterations induced by ECM detachment revealed a dramatic decrease in uptake of glucose, glutamine, and pyruvate, and a consequent decrease in flux through glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle. However, flux through pyruvate dehydrogenase (PDH) is disproportionally decreased, concomitant with increased expression of the PDH inhibitory kinase, PDH kinase 4 (PDK4), and increased carbon secretion. Overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner, and Erk signaling also regulates PDH flux in ECM-attached cells. Additionally, epidermal growth factor (EGF), a potent inducer of Erk, positively regulates PDH flux through decreased PDK4 expression. Furthermore, overexpression of PDK4 in ECM-detached cells suppresses the ErbB2-mediated rescue of ATP levels, and in attached cells, PDK4 overexpression decreases PDH flux, de novo lipogenesis, and cell proliferation. Mining of microarray data from human tumor data sets revealed that PDK4 mRNA is commonly down-regulated in tumors compared with their tissues of origin. These results identify a novel mechanism by which ECM attachment, growth factors, and oncogenes modulate the metabolic fate of glucose by controlling PDK4 expression and PDH flux to influence proliferation.

Key Words: metabolism • glucose • extracellular matrix • pyruvate dehydrogenase • Erk • lipogenesis

Received for publication April 10, 2011. Accepted for publication July 12, 2011.


3 Present address: Department of Bioengineering, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.

4 These authors contributed equally to this work.

5 Corresponding author.

E-mail joan_brugge{at}hms.harvard.edu.

Supplemental material is available for this article.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.16771811.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism.
A. R. Grassian, S. J. Parker, S. M. Davidson, A. S. Divakaruni, C. R. Green, X. Zhang, K. L. Slocum, M. Pu, F. Lin, C. Vickers, et al. (2014)
Cancer Res. 74, 3317-3331
   Abstract »    Full Text »    PDF »
Proliferation-Independent Control of Tumor Glycolysis by PDGFR-Mediated AKT Activation.
C. Ran, H. Liu, Y. Hitoshi, and M. A. Israel (2013)
Cancer Res. 73, 1831-1843
   Abstract »    Full Text »    PDF »
Isocitrate Dehydrogenase (IDH) Mutations Promote a Reversible ZEB1/MicroRNA (miR)-200-dependent Epithelial-Mesenchymal Transition (EMT).
A. R. Grassian, F. Lin, R. Barrett, Y. Liu, W. Jiang, M. Korpal, H. Astley, D. Gitterman, T. Henley, R. Howes, et al. (2012)
J. Biol. Chem. 287, 42180-42194
   Abstract »    Full Text »    PDF »
Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration.
C. A. Caneba, N. Bellance, L. Yang, L. Pabst, and D. Nagrath (2012)
Am J Physiol Endocrinol Metab 303, E1036-E1052
   Abstract »    Full Text »    PDF »
Glucose Oxidation Modulates Anoikis and Tumor Metastasis.
S. Kamarajugadda, L. Stemboroski, Q. Cai, N. E. Simpson, S. Nayak, M. Tan, and J. Lu (2012)
Mol. Cell. Biol. 32, 1893-1907
   Abstract »    Full Text »    PDF »
Extracellular Matrix Regulation of Metabolism and Implications for Tumorigenesis.
A. R. Grassian, J. L. Coloff, and J. S. Brugge (2011)
Cold Spring Harb Symp Quant Biol 76, 313-324
   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