The Eph family of receptor tyrosine kinases and their ligands, the ephrins, have been implicated in the development of the retinotectal projection. Here, glycosylphosphatidylinositol-anchored A-ephrins are not only expressed in the tectum but also on retinal axons, raising the possibility that they function in this context as receptors. We now show that activation of ephrin-A2 or ephrin-A5 by one of their receptors, ephA3, results in a ␤1-integrin-dependent increased adhesion of

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... ingcellstolaminin.Inthesearchforanephrin-Adependent signaling pathway controlling integrin activation, we identified a 120-kDa raft membrane protein that is tyrosine-phosphorylated specifically after ephrin-A activation. Tyrosine phosphorylation of this protein is not seen after stimulating ephrin-A2-expressing cells with basic fibroblast growth factor, epidermal growth factor, insulin growth factor, or fetal calf serum containing a large set of different growth factors. The role of p120 as a mediator of an ephrin-A-integrin coupling is supported by the finding that inhibiting tyrosine phosphorylation of p120 correlates with an abolishment of the ␤1-dependent cell adhesion. During development of the retinotectal projection, members of the Eph family of receptor tyrosine kinases and their "ligands", the ephrins, are strongly involved in guiding retinal axons to, and in, the tectum (for review see Refs. 1-3). Besides the graded expression of Eph receptors on retinal axons and of ephrins in the tectum, the ephrin-As are also differentially expressed on retinal axons themselves (4, 5). Gain of function and loss of function analyses suggest that here the ephrin-As modulate the function of the coexpressed receptors in that coexpression of ligands and receptors runs in parallel to a decrease in sensitivity for the repellent activity of the tectally expressed ephrins (4, 5). These findings fit to subsequent results of in vivo analyses of ephrin-A5 single and ephrin-A5