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.