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 具有独特信号活性的异质复合物，具有生理和致病相关性。 这些异质相互作用可能发生在 20 个 RTK 家族中，但尚未在 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 受体通常在同一细胞中表达，一些证据表明这些共表达 Eph受体可以形成杂复合物。在 Eph 受体中，EphA2 是联系最密切的一种 到疾病。 EphA2 信号传导很复杂，因为它可以介导多种且通常相反的生物信号 功能。例如，EphA2 可以通过不同的方式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。尽管与其他共生体存在异质相互作用 表达的 Eph 受体可能有助于 EphA2 信号传导的多功能性以及 EphA2，这些相互作用的重要性尚不清楚。在本提案中，我们力求加强我们的 通过使用创新技术，了解 EphA2 异质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，我们将使用我们拥有的定量生物物理策略 开发用于表征 EphA2 与其他 Eph 受体的配体独立相互作用。在目标 2 中，我们将 表征在 EphA2 特异性配体存在下 EphA2 与其他 Eph 受体的相互作用。瞄准 3，我们将定义 EphA2 信号传导的特定异质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、效应子招募的影响来完成 下游信号通路以及影响细胞迁移/侵袭的细胞反应。这项工作将 确定相互作用的 Eph 受体影响 EphA2 介导的信号传导过程的机制。这在 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.