Eph Receptor Heterointeractions in Signaling

摘要 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 具有不同信号活性的异源复合体，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家族中的每一个家庭中，但它们还没有在 大多数情况下。Eph家族有14个成员，是最大的受体酪氨酸激酶家族。不同 Eph受体通常在相同的细胞中表达，一些证据表明，这些受体共同表达 Eph受体可以形成异源复合体。在Eph受体中，EphA2是与EphA2联系最深的受体 为了疾病。EphA2信号是复杂的，因为它可以调节不同的，通常是相反的生物 功能。例如，EphA2可以通过不同的途径发挥抗癌或促癌作用。 配体依赖和非配体依赖的信号机制。尽管异质相互作用与其他共同的 表达的Eph受体可能有助于EphA2信号转导的多功能性和EphA2的病理效应 EphA2，这些相互作用的意义还没有被很好地理解。在这项建议中，我们寻求加强我们的 通过使用创新的EphA2异源相互作用的生物学意义的基本知识 工具和实验方法。在目标1中，我们将使用我们已有的定量生物物理策略 开发用于表征EphA2与其他Eph受体的非配体依赖的相互作用。在目标2中，我们将 在存在EphA2特异性配体的情况下，表征EphA2与其他Eph受体的相互作用。在AIM 3，我们将定义EphA2信号的特定异源相互作用的功能后果。这将是 通过研究异质相互作用对EphA2磷酸化、效应器招募、 下游信号通路，以及影响细胞迁移/入侵的细胞反应。这项工作将 确定相互作用的Eph受体影响EphA2介导的信号传递过程的机制。此入站 TURN将为针对混合EphA2-Eph信号平台的未来疗法的设计提供信息。

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.