Regulation of PI3K by PIK3IP1/TrIP

摘要 PI-3激酶（PI 3 K）途径的适当调节对于细胞对许多不同的细胞因子的应答是至关重要的。 细胞外刺激，最终导致改变的增殖、存活和分化。几 该途径的负调控因子已被广泛表征，其中两种也是已知的 肿瘤抑制剂。最近，另一种PI 3 K通路的负调节剂已经被鉴定。 Pik 3 ip 1/TrIP是一种跨膜蛋白，似乎与催化蛋白p110结合并调节其表达。 activation.我们已经招募了一位结构生物学家作为这个项目的合作者，以帮助我们定义如何 TrIP干扰PI 3 K激活。我们还获得了细胞外Kringle结构域 TrIP调节其活性，尽管其机制尚不清楚。在这里我们将探讨 Kringle结构域是否调节TrIP二聚化和/或定位，包括蛋白质的影响。 该结构域的推定配体。我们最近发表的论文，使用诱导型小鼠KO模型，也 显示TrIP的缺失导致T细胞活化增强和细胞内干扰素清除增加。 细菌感染在这里，我们将定义TrIP在原发性和继发性细菌感染中的作用， 病毒感染因此，这项工作将有助于了解PI 3 K活化不仅在T细胞中， 但也可能是其他细胞，因为TrIP在许多其他细胞类型中表达。

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.