Eph Receptor Heterointeractions in Signaling

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SUMMARY Receptor tyrosine kinases (RTKs) can interact with other members of the same RTK family, forming heterocomplexes with distinctive signaling activities that have both physiological and pathogenic relevance. These heterointeractions likely occur within each of the 20 RTK families, but they have not been studied in most cases. The Eph family, with 14 members, is the largest of the receptor tyrosine kinase families. Different Eph receptors are often expressed in the same cells, and some evidence suggests that these co-expressed Eph receptors can form heterocomplexes. Among the Eph receptors, EphA2 is the one most profoundly linked to disease. EphA2 signaling is complex because it can mediate diverse, and often opposite, biological functions. For example, EphA2 can exert either anti-oncogenic or pro-oncogenic effects through different ligand-dependent and ligand-independent signaling mechanisms. Although heterointeractions with other co- expressed Eph receptors likely contribute to the versatility of EphA2 signaling and to the pathological effects of EphA2, the significance of these interactions is not well understood. In this proposal, we seek to enhance our basic knowledge about the biological significance of EphA2 heterointeractions through the use of innovative tools and experimental approaches. In Aim 1, we will use quantitative biophysical strategies that we have developed to characterize ligand-independent interactions of EphA2 with other Eph receptors. In Aim 2, we will characterize EphA2 interactions with other Eph receptors in the presence of an EphA2-specific ligand. In Aim 3, we will define the functional consequences of specific heterointeractions for EphA2 signaling. This will be accomplished by investigating the effects of heterointeractions on EphA2 phosphorylation, effector recruitment, downstream signaling pathways, and cellular responses impacting cell migration/invasion. This work will identify mechanisms by which interacting Eph receptors affect EphA2-mediated signaling processes. This in turn will inform the design of future therapies targeting mixed EphA2-Eph signaling platforms.