Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding, and promotes the Warburg effect [Signal Transduction]
August 7th, 2014 by Fan, J., Kang, H.-B., Shan, C., Elf, S., Lin, R., Xie, J., Gu, T.-L., Aguiar, M., Lonning, S., Chung, T.-W., Arellano, M., Khoury, H. J., Shin, D. M., Khuri, F. R., Boggon, T. J., Kang, S., Chen, J.
The mitochondrial pyruvate dehydrogenase complex (PDC) plays a crucial role in regulation of glucose homoeostasis in mammalian cells. PDC flux depends on catalytic activity of the most important enzyme component pyruvate dehydrogenase (PDH). PDH kinase (PDK) inactivates PDC by phosphorylating PDH at specific serine residues including S293, while dephosphorylation of PDH by PDH phosphatase (PDP) restores PDC activity. The current understanding suggests that S293 phosphorylation of PDH impedes active site accessibility to its substrate pyruvate. Here we report that phosphorylation of a tyrosine residue Y301 also inhibits PDHA1 by blocking pyruvate binding through an independent mechanism in addition to S293 phosphorylation. In addition, we found that multiple oncogenic tyrosine kinases directly phosphorylate PDHA1 at Y301, and Y301 phosphorylation of PDHA1 is common in EGF-stimulated cells as well as diverse human cancer cells and primary leukemia cells from human patients. Moreover, expression of a phosphorylation-deficient PDHA1 Y301F mutant in cancer cells resulted in increased oxidative phosphorylation, decreased cell proliferation under hypoxia, and reduced tumor growth in mice. Together, our findings suggest that phosphorylation at distinct serine and tyrosine residues inhibits PDHA1 through distinct mechanisms to impact active site accessibility, which act in concert to regulate PDC activity and promote the Warburg effect.