PI3K

PI3K

PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. Many of these functions relate to the ability of class I PI 3-kinases to activate protein kinase B (PKB, aka Akt) as in the PI3K/AKT/mTOR pathway.

PI3Ks are a conserved family of proteins involved in several different functions such as . Four different classes of PI3K exist, class IA, IB, II and III based on structural characteristics and substrate specificity. PI3K consists of two subunits-atalytic and regulatory. All the members of PI3K phosphorylate phosphatidylinositides on 3’ position. Such phosphorylated phosphatidylinositides serve as docking sites for other proteins. For example, phosphatdiylinosiol 3, 4 bisphosphate (PIP2) and phosphatidylinositol 3,4,5 trisphosphate (PIP3) bind to pleckstrin homology (PH) domain-containing proteins such as Akt, Btk, Vav etc. Similarly phosphatidylinositol 3 phosphate (PI3P) serves as a docking site for proteins with phox homology (PX) domain such as p47phox, one of the important components of phagocytic oxidase system.

PI3Ks have been implicated in several effector functions of macrophages such as phagocytosis, chemotaxis, and toxic metabolites production. The following paragraphs describe the role of PI3K in some of its effector functions. PI3K is critical for phagocytosis initiated through receptors such as Fcγ and complement receptors. The importance of PI3K in phagocytosis is more prominent in the engulfment of larger particles (> 4.5μm). The function of PI3K in the phagocytic uptake is interesting. Although PI3K is dispensable for the particle binding and subsequent phagocytic cup formation but it is critical for pseudopod extension and the ensuing phagocytic cup closure. Downstream of PI3K, Akt and Rac were reported to be essential for the phagocytosis of IgG-opsonized Sheep-RBC (S-RBC). In addition to the role of PI3K in Fcγ R-mediated phagocytosis, Allen et al reported that it is required for the delayed of phagocytosis of ulcerogenic Helicobacter pylori. However, PI3K independent phagocytosis was also reported in the internalization of Salmonella and Shigella. PI3K is also required for chemotaxis. Attesting to the importance of PI3K in chemotaxis, the inhibition of Akt, a downstream-effector of PI3K, significantly dampened fMLP-stimulated neutrophil chemotaxis. PI3K is also required for the generation of toxic metabolites such as superoxide and nitric oxide. First, Rac2 (PI3K-dependent protein), an abundant isoform of Rac in neutrophils, is an essential component of the phagocytic oxidase (or NADPH oxidase) complex that catalyzes the production of superoxide. Second, PI3K was reported to be critical for the phosphorylation of p47phox, an essential component of phagocytic oxidase. Specifically, PI3K effector Akt was demonstrated to interact with and phosphorylate p47phox. Thus, Akt regulates the fMLP-induced respiratory burst in human neutrophils. Third, macrophages deficient in PI3K are impaired in the production of LPS and IFNγ induced nitric oxide production. In this study, Sakai et al. found that the expression of inducible nitric oxide synthase (iNOS), an enzyme involved in the generation of nitric oxide, is unchanged in PI3K-deficient macrophages but the dimerization of iNOS protein is significantly impaired.

PI3K has an indispensable role in modulating the production of cytokines in response to pathogenic stimuli. The role of PI3K in inflammation is controversial. Some studies demonstrate that PI3K promotes inflammation but few studies suggest that PI3K/Akt pathway may act as a negative regulator and limit pro-inflammatory response in response to infectious stimuli. Briefly, PI3K/Akt pathway was reported to promote LPS-induced IL-10 production by macrophages suggesting a negative role for PI3K. Also, in another study inhibition of PI3K using a wortmannin in vivo resulted in increased serum levels of IL-1β, TNFα, IL-6 etc. thereby enhancing the susceptibility to polymicrobial sepsis. In contrast, blockade of PI3K/Akt pathway by specific inhibitor inhibited immune complex-induced IL-6 production but not IL-1β production in bone marrow derived macrophages suggesting that PI3K/Akt is a positive regulator of Fcγ Rmediated cytokine response. Further, Fukao et al reported that p85α (one of the subunits of PI3K) knockout mice showed impaired clearance of enterobacteria injected into the peritoneal cavity. These discrepancies regarding the requirement of PI3K in inflammation may be due to the differences in the cellular context and/or the stimuli used. Future studies may enhance our understanding about the role of PI3K in inflammation.

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