An ephrin-A-dependent signaling pathway controls integrin function and is linked to the tyrosine phosphorylation of a 120-kDa protein

The Eph family of receptor tyrosine kinases and their ligands, the ephrins, have been implicated in the development of the retinotectal projection. He re, 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 ephri n-A2 or ephrin-A5 by one of their receptors, ephA3, results in a beta1-inte grin-dependent increased adhesion of ephrin-A-expressing cells to laminin. In the search for an ephrin-A-dependent signaling pathway controlling integ rin activation, we identified a 120-kDa raft membrane protein that is tyros ine-phosphorylated specifically after ephrin-A activation. Tyrosine phospho rylation of this protein is not seen after stimulating ephrin-A2-expressing cells with basic fibroblast growth factor, epidermal growth factor, insuli n growth factor, or fetal calf serum containing a large set of different gr owth factors. The role of p120 as a mediator of an ephrin-A-integrin coupli ng is supported by the finding that inhibiting tyrosine phosphorylation of p120 correlates with an abolishment of the beta1-dependent cell adhesion.