Adapters in the organization of mast cell signaling

FcεRI aggregation by cell surface-bound IgE antibody interaction with a multivalent antigen leads to the phosphorylation of the receptors β- and γ-chain immunoreceptor tyrosine-based activation motifs (ITAMs) by Lyn kinase. Fyn and Syk kinases are then recruited to the receptor and initiate complementary signals that cooperate in MC responses. Fyn and possibly Syk phosphorylate adapters like Gab2 that are essential for PI3K activation. Syk also phosphorylates the adapters LAT1 and LAT2 in several tyrosine residues. LAT1 organizes a complex that binds phospholipase C-γ (PLC-γ), SLP-76, and son-of-sevenless (SOS) via adapters such as Gads, Grb2, and Shc. Activation of PLC-γ in this complex causes the 2+ hydrolysis of PI(, )P2 into IP3 and DAG, increasing intracellular Ca concentrations and activating PKC. In addition to LAT1, the adapter LAT2 is also phosphorylated after FcεRI aggregation and organizes a signaling complex by recruiting Grb2 to its several YXN motifs. Grb2 then participates in activating the PI3K pathway through its association with the adapter Gab2. Like LAT1, LAT2 is able to recruit the guanine nucleotide exchange factors Vav1 and SOS, which in turn activate MAPKs such as ERK. LAT2 may also bind PLC-γ indirectly by its association with Grb2. LAT1 is well documented to be involved in Ca2+ mobilization, which is crucial for MC degranulation, NFAT activation, and cytokine production. PKC activation is also essential for MC degranulation, activation of NF-κB, and cytokine production.

Publication

Adapters in the organization of mast cell signaling. () Damiana Alvarez-Errico, et al. Immunol Rev. ;232(1):195-217. Figure: F1. Homo sapiens

Disease mentions