The multiple roles of phosphoinositide 3-kinase in mast cell biology

Abstract

Mast cells play a central role in the initiation of inflammatory responses associated with asthma and other allergic disorders. Receptor-mediated mast cell growth, differentiation, homing to their target tissues, survival and activation are all controlled, to varying degrees, by phosphoinositide-3-kinase (PI3K)-driven pathways. It is not fully understood how such diverse responses can be differentially regulated by PI3K. However, recent studies have provided greater insight into the mechanisms that control, and those that are controlled by, different PI3K subunit isoforms in mast cells. In this review, we discuss how PI3K influences the mast cell processes described above. Furthermore, we describe how different mast cell receptors use alternative isoforms of PI3K for these functions and discuss potential downstream targets of these isoforms.

Figure 1

Structure and function of PI3K subunit isoforms expressed in mast cells. The emphasized catalytic subunit isoforms are those that have been documented to play specific roles in mast cell responses as outlined in the text column. Whereas there is little selectivity in utilization of the p85 subunits for FcεRI-mediated responses, Kit responses show selective requirements for the p85α subunit (emphasized). Abbreviations: BH: Bcr/Rac GAP homology domain; C2: protein kinase C homology domain 2; GPCR; G protein-coupled receptor; SH: Src homology domain. ¹As determined by passive cutaneous anaphylaxis reaction. ²Likely indirectly following release of adenosine or other GPCR ligand. ³GPCRs binding adenosine, MIP-1α (CCL3), Rantes (CCL5), or platelet activating factor. ⁴As determined by passive systemic anaphylaxis reaction.

Figure 2

Positive and negative regulation of PI3K-dependent signaling pathways in activated mast cells. (A) Activation of class 1A PI3Ks by Kit and FcεRI and class 1B PI3K by GPCRs at the inner cell membrane. The SH2 domains of the p85 regulatory subunits of class 1A PI3K can directly bind to phosphorylated Kit, whereas the association of p85s with the FcεRI is indirect via the cytosolic adaptor molecule, Gab2. The p101 regulatory subunit of class 1B PI3K directly binds to free G protein βγ homodimers that are dissociated from heterotrimeric G-proteins after GPCR activation. The catalytic subunits of PI3K, p110δ and p110γ, phosphorylate the inositol ring of phosphoinositides at the D3 hydroxyl position, thereby converting phosphatidylinositol-(4,5)-bisphosphate (PtdInsP₂) to phosphatidylinositol-(3,4,5)-triphosphate (PtdInsP₃) at the inner plasma membrane. This leads to the regulation of the downstream signaling events in activated mast cells depicted in Figure 3. (B) Activation of PTEN and SHIP by FcεRI and inhibitory receptors. PTEN removes the phosphate group from the D3 position of the inositol ring whereas SHIP removes the phosphate from the D5 position of the inositol ring, converting PtdInsP₃ to PtdIns(4,5)P₂ and PtdIns(3,4)P₂, respectively. Thus, PtdInsP₃ levels decrease, and the effect of PI3K activation is negatively regulated by PTEN and SHIP. SHIP interacts with FcεRI in a Lyn-dependent manner and with inhibitory receptors such as FcγRIIb and MAFA, through association with their ITIM motifs.

Figure 3

Downstream targets of PI3K in activated mast cells. Activation of class 1 PI3Ks generates the membrane-associated PtdInsP₃ at the inner membrane, which provides inducible docking sites for pleckstrin homology (PH) domains of associating signaling molecules. The Ser/Thr kinases, PDK1 and AKT are subsequently phosphorylated and activated after Kit and FcεRI activation. Major downstream targets of PI3K and AKT in mast cells, mTORC1, Btk, FOXO3a, and GSK3β pathways are shown (also see text) together with the specific responses in activated mast cells. Although depicted in the figure, and documented in other systems, it is not known whether AKT activation is regulated by the mTORC2 complex in mast cells. In addition, the function of GSK3β in activated mast cells still requires clarification. Whether these events are also initiated by GPCRs is currently unknown. For clarity other signaling events required for FcεRI-and Kit-mediated responses in mast cells are not depicted in this figure. Readers are referred to recent review articles for further details of these processes [6,10].