Regulation of PI3K by PIK3IP1/TrIP

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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.