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EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

Oncogene volume 28, pages 1759–1768 (2009)Cite this article

Abstract

Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands play important roles in nervous system development. Recently, they have been implicated in tumorigenesis of different cancers. In this study, we showed that the expression of ephrinA5 was dramatically downregulated in primary gliomas compared with normal tissues. Forced expression of ephrinA5 reduced tumorigenicity of human glioma U373 cells. Epidermal growth factor receptor (EGFR), which frequently acts as an oncoprotein in glioma, was greatly decreased in ephrinA5-transfected glioma cells, and the two molecules exhibited a mutually exclusive expression pattern in primary glioma samples. We found that ephrinA5 enhanced c-Cbl binding to EGFR, thus promoted ubiquitylation and degradation of the receptor. Either ephrinA5-Fc or EphA2-Fc treatment simulating bidirectional signaling of Eph/ephrin system resulted in EGFR decrease. This study discovered that ephrinA5 acted as a tumor suppressor in glioma, and its negative regulation of EGFR contributed to the suppressive effects. In addition to identifying a novel mechanism underlying tumor suppressor activity of ephrinA5, we also showed cross-talk between different receptor tyrosine kinase families in glioma. These findings may improve therapeutic strategies for glioma.

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Acknowledgements

We thank Dr Alfred C Johnson for the EGFR promoter reporter plasmid, Dr Yosef Yarden for the hEGFR and hEGFR (Y1045F) plasmids, Dr De Camilli P for pcDNA3.1-HA-Ubiquitin plasmid and Dr Hans-Christian Aasheim for CD19-Fc and EphA2-Fc constructs.

We also would like to thank Dr H Phillip Koeffler (Cedars-Sinai Medical Center) for helpful discussions, suggestions and critical reading of this paper.

This work was supported by Ministry of Science and Technology 863 Program 2007AA02Z474, 973 Program 2007CB914704, and 2008ZX10207, National Natural Science Funds for Distinguished Young Scholar 30725010, National Natural Science Foundation of China 90813023 and 30528003. Chinese Academy of Sciences Grant KSCX2-YW-R-152 and KSCX-YW-R-73, and Science and Technology Commission of Shanghai Municipality 08140902300 to D Xie.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Shanghai, People's Republic of China

    J-J Li, D-P Liu & D Xie

  2. Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China

    J-J Li

  3. Cedars-Sinai Medical Center, Los Angeles, CA, USA

    G-T Liu

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  1. J-J Li
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Correspondence to D Xie.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Li, JJ., Liu, DP., Liu, GT. et al. EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor. Oncogene 28, 1759–1768 (2009). https://doi.org/10.1038/onc.2009.15

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