Multiple signaling interactions of Abl and Arg kinases with the EphB2 receptor

The Eph family of receptor tyrosine kinases and the Abl family of non-recep tor tyrosine kinases have both been implicated in tissue morphogenesis, The y regulate the organization of the actin cytoskeleton in the developing ner vous system and participate in signaling pathways involved in axon growth, Both Eph receptors and Abl are localized in the neuronal growth cone, sugge sting that they play a role in axon pathfinding. Two-hybrid screens identif ied regions of Abl and Arg that bind to the EphB2 and EphA4 receptors, sugg esting a novel signaling connection involving the two kinase families. The association of full-length Abl and Arg with EphB2 was confirmed by co-immun oprecipitation and found to involve several distinct protein interactions. The SH2 domains of Abl and Arg bind to tyrosine-phosphorylated motifs in th e juxtamembrane region of EphB2, A second, phosphorylation-independent inte raction with EphB2 involves non-conserved sequences in the C-terminal tails of Abl and Arg, A third interaction between Abl and EphB2 is probably medi ated by an intermediary protein because it requires tyrosine phosphorylatio n of EphB2, but not the binding sites for the Abl SH2 domain. The connectio n between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 cause s tyrosine phosphorylation of Abl and Arg, and vice vel sa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activa te endogenous EphB2 decreased the kinase activity of endogenous Abl, These data are consistent,vith the opposite effects that Eph receptors and Abl ha ve on neurite ougrowth and suggest that Eph receptors and Abl family kinase s have shared signaling activities.