Eph receptors, the largest receptor tyrosine kinases, and their ephrin ligands 
play important roles in axon guidance and cell migration during development of 
the nervous system. Recently, these molecules are also found involved in 
tumorigenesis of different kinds of cancers. In this study, we demonstrated that 
expression of ephrin-A1 was dramatically down-regulated in glioma cell lines and 
in primary gliomas compared to the matched normal tissues. Forced expression of 
ephrin-A1 attenuated cell migration, cell proliferation, and 
adhesion-independent growth in human glioma U251 cells. EphA2, a receptor for 
ephrin-A1 and an oncoprotein, was greatly decreased in ephrin-A1-transfected 
glioma cells. Overexpression of ephrin-A1 stimulated activation of EphA2 by 
phosphorylation and led to its degradation. Furthermore, focal adhesion kinase 
(FAK), a known downstream molecule of EphA2, was also down-regulated in the 
ephrin-A1 transfected cells. These results suggested that ephrin-A1 serves as a 
critical negative regulator in the tumorigenesis of gliomas by down-regulating 
EphA2 and FAK, which may provide potential valuable targets for therapeutic 
intervention.