Trends in Immunology
ReviewThe multiple roles of phosphoinositide 3-kinase in mast cell biology
Section snippets
Regulation of mast cell processes by Kit and FcɛRI
Mast cells are important effector cells that contribute to the body's ability to respond defensively to invading pathogens and parasites 1, 2. However, activation of mast cells can have disabling consequences by initiating allergic inflammatory reactions in response to antigen that are associated with atopic asthma, allergic rhinitis, eczema and anaphylaxis [3]. In addition, mast cells have also been implicated in rheumatoid arthritis, multiple sclerosis, atherosclerosis, inflammatory bowel
Expression and regulation of PI3K in mast cells
PI3Ks comprise a family of lipid kinases (Box 2) that play crucial roles in multiple biological responses 11, 12, 13. Class 1 PI3Ks, the major hematopoietic forms of PI3K (Figure 1; Box 2), are heterodimeric comprising a regulatory and catalytic subunit. Mast cells express the class 1A p85α, p85β and p50α regulatory subunit isoforms 14, 15 in addition to all three class 1A PI3K catalytic subunit isoforms, p110α, p110β, and p110δ and the class 1B p110γ catalytic subunit 16, 17 (Figure 1). As Kit
Mast cell degranulation and cytokine production
A role for PI3K in mast cell activation has been revealed by several approaches as outlined in Box 3. The PI3K inhibitors, wortmannin and LY294002, have been widely reported to inhibit antigen-mediated degranulation and cytokine production in both rodent and human mast cells 14, 32, 39. However, at least in human mast cells, these compounds fail to completely inhibit degranulation suggesting that, although PI3K is essential for optimal degranulation of mast cells, PI3K-independent pathways
Negative regulation of PI3K-dependent mast cell responses by PTEN and SHIP
PtdInsP3 levels, and hence PI3K-regulated signaling pathways in mast cells and other cell types, are finely regulated by the balance between phosphorylation induced by PI3Ks and dephosphorylation regulated by the inositol phosphatases, PTEN and SHIP (Box 2; Figure 2b). In quiescent human mast cells, shRNA-induced knockdown of PTEN results in increased basal PtdInsP3 levels and constitutive phosphorylation of AKT and the mitogen-activated protein (MAP) kinases, p38 and c-Jun N-terminal kinase
Downstream effectors regulated by PI3K
The above discussions demonstrate that PI3K regulates diverse responses in activated mast cells. From studies conducted in multiple cell types, it is evident that PI3K can influence a wide range of signaling molecules and pathways [57]. Systematic studies, using a variety of approaches (Box 3), are now beginning to address which of these PI3K-regulated signaling processes regulate specific mast cell responses. In the following section and in Figure 3, we describe what is currently known about
Summary, conclusions and future considerations
In summary, it is now clear that PI3K-regulated signaling events play a central role in mast cell biology. The downstream targets responsible for the receptor-mediated, PI3K-dependent responses in mast cells have still not been fully elucidated. However, PI3K-regulated degranulation, and to a certain extent cytokine production, seems to be linked to the regulation of a latent calcium signal, likely requiring activation of Btk. Multiple PI3K-regulated processes seem to contribute to mast cell
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgements
Research in the authors’ laboratory is supported by the NIAID Intramural Program within the National Institutes of Health. The authors thank Michael A. Beaven LMI/NHLBI/NIH for critical review of the manuscript and the editor and the reviewers of this manuscript for helpful comments. Because of space constraints, not all pertinent literature could be referenced in this article. This does not imply that other articles not referenced are of lesser merit.
References (93)
Signaling by Kit protein-tyrosine kinase–the stem cell factor receptor
Biochem. Biophys. Res. Commun.
(2005)- et al.
Molecular regulation of mast cell activation
J. Allergy Clin. Immunol.
(2006) - et al.
Signaling by distinct classes of phosphoinositide 3-kinases
Exp. Cell Res.
(1999) The phospholipase Cγ1-dependent pathway of FcɛRI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase
J. Biol. Chem.
(2003)Impaired kit- but not FcɛRI-initiated mast cell activation in the absence of phosphoinositide 3-kinase p85α gene products
J. Biol. Chem.
(2000)Antigen receptor signalling: a distinctive role for the p110δ isoform of PI3K
Trends Immunol.
(2007)Molecular basis for a direct interaction between the Syk protein-tyrosine kinase and phosphoinositide 3-kinase
J. Biol. Chem.
(2005)Genetic evidence for convergence of c-Kit- and α4 integrin-mediated signals on class IA PI-3 kinase and the Rac pathway in regulating integrin-directed migration in mast cells
Blood
(2003)Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration
Blood
(2002)Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase
J. Biol. Chem.
(2001)