Figure 2
From: The human immunoglobulin A Fc receptor FcαRI: a multifaceted regulator of mucosal immunity
Simplified scheme of signaling pathways involved in FcαRI functioning. (a) Inside–out signaling or priming of FcαRI. The intracellular domain of FcαRI, an intact cytoskeleton, phosphorylation of serine 263, phosphatidylinositol 3 kinase (PI3K), and its downstream target protein kinase C (PKC) and serine/threonine phosphatase protein protein phosphatase 2A (PP2A) are involved in switching inactive FcαRI into an active, ligand binding receptor after cytokine stimulation. (b, Left) Crosslinking of FcαRI by immunoglobulin A (IgA)–immune complexes induces redistribution of FcαRI to plasma membrane rafts. Src kinase Lyn phosphorylates the tyrosines within the associated FcR γ-chain-immunoreceptor tyrosine-based activation motif (ITAM). These then serve as “docking” sites for recruitment of B lymphocyte kinase (Blk), Syk, phospholipase (PLC)-γ, Shc, and growth factor receptor-bound protein 2 (Grb2), which facilitates activation of multiple (and subsequential) targets such as PI3K, PLC-γ, and components of a Grb2 containing multimolecular adapter protein complex. This results in cellular functions such as phagocytosis, Ab-dependent-cellular cytotoxicity, respiratory burst, degranulation, antigen-presentation, and release of cytokines and inflammatory mediators. (Right) Triggering FcαRI with monomeric serum IgA (not crosslinking FcαRI) transduces inhibitory signals through FcαRI–FcR γ-chain complex via inhibitory capacity through FcR γ-chain ITAM (ITAMi), which downregulates other activating Fc receptors. The inhibitory signal involves recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) to FcαRI, and formation of inhibisome clusters (dotted lines), which impair phosphorylation of Syk, LAT, and ERK. Ca2+, calcium; Cbl, Casitas B-lineage lymphoma; DAG, diacylglycerol; GDP, guanosine diphosphate; GTP, guanosine triphosphate; LAT, linker of activated T cells; p, phosphate; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; SLP-76, SH2 domain containing leukocyte protein of 76 kDa; SHIP, Src homology-2-containing inositol 5′-phosphatase.
