The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ.

Edwards DN, Ngwa VM, Wang S, Shiuan E, Brantley-Sieders DM, Kim LC, Reynolds AB, Chen J
Sci Signal. 2017 10 (508)

PMID: 29208682 · PMCID: PMC5819349 · DOI:10.1126/scisignal.aan4667

Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing or substantially reduced the amount of intracellular glutamate through decreased expression of and , respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both and contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, expression positively correlated with that of and , as well as that of and Although high expression of predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify potential therapeutic targets in patients.

Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

MeSH Terms (20)

Adaptor Proteins, Signal Transducing Amino Acid Transport System ASC Animals Biomarkers, Tumor Breast Neoplasms Disease Models, Animal DNA-Binding Proteins Ephrin-A2 Female Glutaminase Glutamine Humans Intracellular Signaling Peptides and Proteins Mice Mice, Knockout Minor Histocompatibility Antigens Muscle Proteins Phosphoproteins Transcription Factors Tumor Cells, Cultured

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