Mast Cells Require the Gift of Gab2

Abstract

Activation of the immunoglobulin E (IgE) receptor FcϵR1 is necessary for the allergic response, which results in exocytosis of histamine- and serotonin-containing granules (termed degranulation) from mast cells. The protein tyrosine kinases Lyn and Syk mediate FcϵR1 signaling events leading to the activation of the Ras and phosphatidylinositol 3-kinase (PI3K) pathways. Recent biochemical studies implicate the adaptor protein Gab2 in PI3K signaling and pathways originating at multichain immune recognition receptors (MIRRs) such as the T cell- and B cell-antigen receptors. Gu et al . now provide genetic evidence that Gab2 is important for FcϵR1-dependent PI3K activity and the allergic response. Bone marrow-derived mast cells (BMMCs) from Gab2 -/- mice exhibited less FcϵR1-mediated degranulation in response to antigen. This resulted from decreased activation of phospholipase C-γ1, whose activity is required for Ca 2+ - and PKC-dependent degranulation. Expression of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) mRNAs was also decreased in Gab2 -/- BMMCs. Anaphylactic shock responses were also diminished in Gab2 -/- mice. These results indicate that Gab2 plays a role in the generation of allergic responses in mast cells. The authors found that the absence of Gab2 in BMMCs resulted in defective activation of PI3K (probably as a result of impaired recruitment of PI3K to Lyn and Syk), and weak activation of Akt and the mitogen-activated protein kinases (MAPKs) p38 and JNK (Jun NH 2 -terminal kinase), which are important for stimulating cytokine expression. Thus, Gab2 appears to be essential for regulating proper FcϵR1-mediated mast cell degranulation and cytokine expression in the allergic response. H. Gu, K. Saito, L. D. Klaman, J. Shen, T. Fleming, Y. P. Wang, J. C. Pratt, G. Lin, B. Lim, J.-P. Kinet, B. G. Neel, Essential role for Gab2 in the allergic response. Nature 412 , 186-190 (2001). [Online Journal]