Regulation of PI3K by PIK3IP1/TrIP

摘要 PI-3激酶(PI3K)通路的正确调节对于细胞对许多不同的 细胞外刺激，最终导致细胞增殖、存活和分化的改变。几个 这一途径的负调控因子已经被广泛描述，其中两个也是已知的 肿瘤抑制因子。最近，又发现了PI3K途径的另一个负调控因子。 PIK3IP1/TRIP是一种跨膜蛋白，它似乎与催化蛋白p110结合并调节其 激活。我们招募了一位结构生物学家作为这个项目的合作者，帮助我们定义 TRIP干扰PI3K的激活。我们还获得了细胞外kringle结构域的证据 尽管其机制尚不清楚，但TRIP的作用机制仍不明确。在这里我们将探索 Kringle结构域是否调节TRIP二聚化和/或局部化，包括 这个结构域的假定配体。我们最近发表的论文，使用了一种可诱导的小鼠KO模型，也 显示TRIP的丢失导致T细胞的激活增强和细胞内的清除增加 细菌感染。在这里，我们将定义TRIP在初级和次级细菌和 病毒感染。因此，这项工作将有助于了解PI3K激活是如何不仅在T细胞中调节的， 但也可能是其他细胞，因为TRIP在许多其他类型的细胞中都有表达。

Abstract Proper regulation of the PI-3 kinase (PI3K) pathway is critical for cellular responses to many different extracellular stimuli, ultimately resulting in altered proliferation, survival and differentiation. Several negative regulators of this pathway have been extensively characterized, two of which are also known tumor suppressors. Recently, another negative regulator of the PI3K pathway has been identified. Pik3ip1/TrIP is a transmembrane protein that appears to bind the catalytic protein p110 and modulate its activation. We have recruited a structural biologist as a collaborator on this project to help us define how TrIP interferes with PI3K activation. We have also obtained evidence that the extracellular kringle domain of TrIP regulates its activity, although the mechanisms for this are not yet clear. Here we will explore whether the kringle domain regulates TrIP dimerization and/or localization, including the impact of a putative ligand for this domain. Our recently published paper, using an inducible mouse KO model, also shows that loss of TrIP leads to enhanced activation of T cells and increased clearance of an intracellular bacterial infection. Here we will define the effects of TrIP during primary and secondary bacterial and viral infection. This work will therefore help to inform how PI3K activation is regulated not only in T cells, but possibly other cells as well, since TrIP is expressed in a number of other cell types.