Proper regulation of the PI-3 kinase (PI3K) pathway is critical for normal development, activation and homeostasis in many tissues, including in mast cells. Several negative regulators of the PI3K pathway have been extensively characterized, two of which are known tumor suppressors. Recently, another negative regulator of the PI3K pathway was identified. PIK3IP1 is a transmembrane protein that may act by binding the catalytic protein p110 and preventing its activation. Thus far, very little is known about the possible role of PIK3IP1 in the regulation of leukocyte development or activation. We have found that PIK3IP1 is expressed in mast cells. Importantly, we have now found that mast cells from PIK3IP1 knockout mice are hyper-sensitive to activation by IgE and antigen, which acts through the receptor FceRI. We will therefore determine the effects of PIK3IP1 on specific signaling pathways downstream of FceRI on mast cells, including the role of specific domains within PIK3IP1 for this activity and how it might be modulated by interaction of PIK3IP1 with potential ligands.
Completion of this project will allow us to determine, for the first time, the role of the novel protein PIK3IP1 in mast cell activation and function. These studies may open the door to further in vivo characterization of the function of this novel regulator of the PI3K pathway in normal and pathological aspects of mast cell biology. Given what is known about the role of PI3K in human disease, this may include information relevant for the diagnosis or treatment of various cancers, allergic and/or autoimmune diseases.
|Uche, Uzodinma U; Piccirillo, Ann R; Kataoka, Shunsuke et al. (2018) PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt. J Exp Med 215:3165-3179|