PI3K Signaling in Neutrophils

Abstract

PI3Ks play important roles in the signaling pathways used by a wide variety of cell surface receptors on neutrophils. Class IB PI3K plays a major role in the initial generation of PtdIns(3,4,5)P₃ by Gi-coupled G-protein coupled receptors (GPCRs) (e.g., receptors for fMLP, C5a, LTB₄). Class IA PI3Ks generate PtdIns(3,4,5)P₃ downstream of receptors which directly or indirectly couple to protein tyrosine kinases such as integrins, FcγRs, cytokine receptors, and GPCRs. The PtdIns(3,4,5)P₃ made by Class I PI3Ks regulates the activity of several different effector proteins, many of which are plasma membrane GEFs or GAPs for small GTPases. Class III PI3K generates PtdIns(3)P in the phagosome membrane and plays an important role in efficient assembly of the NADPH oxidase at this location. Much still remains to be discovered about the molecular details that govern activation of PI3Ks and the mechanisms by which these enzymes regulate complex cellular processes, such as neutrophil spreading, chemotaxis, phagocytosis, and killing of pathogens. However, it is clear from recent use of transgenic mouse models and isoform-selective PI3K inhibitors that these pathways are important in regulating neutrophil recruitment to sites of infection and damage in vivo. Thus, PI3K pathways may present novel opportunities for selective inhibition in some inflammatory pathologies.