Abstract
The ephrinA1 ligand exerts antioncogenic effects in tumor cells through activation and downregulation of the EphA2 receptor and has been described as a membrane-anchored protein requiring clustering for function. However, while investigating the ephrinA1/EphA2 system in the pathobiology of glioblastoma multiforme (GBM), we uncovered that ephrinA1 is released from GBM and breast adenocarcinoma cells as a soluble, monomeric protein and is a functional form of the ligand in this state. Conditioned media containing a soluble monomer of ephrinA1 caused EphA2 internalization and downregulation, dramatic alteration of cell morphology and suppression of the RasāMAPK pathway. Moreover, soluble monomeric ephrinA1 was functional in a physiological context, eliciting collapse of embryonic neuronal growth cones. We also found that ephrinA1 is cleaved from the plasma membrane of GBM cells, an event which involves the action of a metalloprotease. Thus, the ephrinA1 ligand can, indeed, function as a soluble monomer and may act in a paracrine manner on the EphA2 receptor without the need for juxtacrine interactions. These findings have important implications for further deciphering the function of these proteins in pathology and physiology, as well as for the design of ephrinA1-based EphA2-targeted antitumor therapeutics.
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Acknowledgements
This study was supported by the NIH Grant 1 F31 NSO55533-01 to JW, NIH Grant 5 T32 CA113267-04 to Dr Mike Robbins (EP) and Brain Tumor Center of Excellence at Wake Forest University School of Medicine. We thank Dr Hannah Caldas and Ms Amanda Beauchamp for help with real-time PCR and Ms Carla Lema-Tome for preparing cortical neurons.
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Wykosky, J., Palma, E., Gibo, D. et al. Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. Oncogene 27, 7260ā7273 (2008). https://doi.org/10.1038/onc.2008.328
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DOI: https://doi.org/10.1038/onc.2008.328
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