Eph Receptor Heterointeractions in Signaling

总结 受体酪氨酸激酶（RTK）可以与同一RTK家族的其他成员相互作用，形成 具有独特的信号传导活性的杂合物具有生理和致病相关性。 这些异源相互作用可能发生在20个RTK家族中的每一个家族中，但它们尚未被研究。 大多数情况下。Eph家族有14个成员，是受体酪氨酸激酶家族中最大的。不同 Eph受体通常在相同的细胞中表达，一些证据表明， Eph受体可形成杂合物。在Eph受体中，EphA 2是与Eph受体之间 疾病。EphA 2信号传导是复杂的，因为它可以介导不同的，并且通常相反的生物学特性， 功能协调发展的例如，EphA 2可以通过不同的细胞因子发挥抗癌或促癌作用。 配体依赖性和配体非依赖性信号传导机制。虽然与其他合作伙伴的互动- 表达的Eph受体可能有助于EphA 2信号传导的多功能性和EphA 2的病理作用。 EphA 2，这些相互作用的意义还没有很好地理解。在这项建议中，我们力求加强我们的 关于EphA 2异源相互作用的生物学意义的基本知识，通过使用创新的 工具和实验方法。在目标1中，我们将使用我们现有的定量生物物理策略， 开发用于表征EphA 2与其他Eph受体的配体非依赖性相互作用。在目标2中，我们 表征在EphA 2特异性配体存在下EphA 2与其它Eph受体的相互作用。在Aim中 3，我们将定义EphA 2信号传导的特定异源相互作用的功能后果。这将是 通过研究异源相互作用对EphA 2磷酸化，效应子募集， 下游信号传导途径和影响细胞迁移/侵袭的细胞应答。这项工作将 鉴定相互作用的Eph受体影响EphA 2介导的信号传导过程的机制。这 反过来将为未来针对混合EphA 2-Eph信号平台的治疗设计提供信息。

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.