Phosphorylated Y452, Y476, and Y584 of GAB2 binds p85 regulatory subunit of PI3K kinase, resulting in activation of PI3K pathway. PI3K is required for mast cell degranulation and anaphylaxis response but not for cytokine production or contact hypersensitivity (Nishida et al. 2011). Activated PI3K generates second messenger PtdInsP3 (PIP3) at the inner membrane, which provides docking sites for pleckstrin homology (PH) domains of PDK1, AKT and BTK. Activated AKT controls major downstream targets like mTORC1, FOXO3 and GSK3beta pathways that regulate mast cell growth, homeostasis, and cytokine production. BTK triggers PLCgamma2 activation, thereby inducing activation of the transcription factor NFAT and NF-kB.
Hirano, T, Ishihara, K, Itoh, M, Fukada, T, Yoshida, Y, Hibi, M, Shirogane, T, Takahashi-Tezuka, M, Nishida, K, Atsumi, T, Ohtani, T
Gu, H, Lowell, CA, Yu, M, Neel, BG
Koseki, H, Hasegawa, A, Hirano, T, Nishida, K, Iwamatsu, A, Yamasaki, S
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