Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Alexandra R. Grassian^1,4, Christian M. Metallo^2,3,4, Jonathan L. Coloff¹, Gregory Stephanopoulos²,, and Joan S. Brugge^1,5

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.

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.

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