Fcε受体（FCERI）信号传导
中文名称
通路描述
肥大细胞（MC）遍布人体各处组织，长期以来已被认为是 I 型超敏反应的关键细胞。它们在炎症和即时过敏反应中也发挥重要作用。通过 FCERI 结合抗原特异性 IgE 引起的激活，会释放强效的炎症介质，如组胺、蛋白酶、趋化因子、细胞因子和花生四烯酸代谢产物，这些介质作用于血管、平滑肌、结缔组织、黏液腺和炎症细胞（Borish & Joseph 1992, Amin 2012, Metcalfe 等人 1993）。FCERI 是一种多聚体细胞表面受体，与 IgE 的 Fc 片段具有高亲和力。在肥大细胞和基细胞上，FCERI 以四聚体复合物形式存在，由一个α链、一个β链和两个二硫键连接的γ链组成；在树突状细胞、朗格汉斯细胞、巨噬细胞和嗜酸性粒细胞上，它则以三聚体复合物形式存在，由一个α链和两个二硫键连接的γ链组成（Wu 2011, Kraft & Kinet 2007）。肥大细胞中的 FCERI 信号传导涉及一系列信号分子和适配蛋白网络。这些分子最终协调导致脱颗粒、前列腺素产生、细胞因子和趋化因子产生以及细胞迁移和粘附、生长和生存。FCERI 信号传导的第一步是 LYN（结合在 FCERIβ链上）磷酸化 FCERIβ和γ亚基 ITAM 中的酪氨酸残基。磷酸化的 ITAM 则招募蛋白酪氨酸激酶 SYK（脾酪氨酸激酶），后者磷酸化适配蛋白 LAT。磷酸化的 LAT（T 细胞激活接头蛋白）作为支架蛋白，招募其他胞质适配分子 GRB2（生长因子受体结合蛋白 2）、GADS（GRB2 相关接头蛋白）、SHC（SRC 同源 2 结构域转化蛋白 C）和 SLP76（76 kDa 白细胞 SH2 结构域蛋白），以及交换因子和接头分子 VAV 和 SOS（sevenless homologue），以及信号酶磷脂酶 Cγ1（PLCγ1）。酪氨酸磷酸化酶和适配分子，包括 VAV、SHC、GRB2 和 SOS，刺激小 GTP 酶如 RAC、RAS 和 RAF。这些通路导致 ERK、JNK 和 p38 MAP 激酶的激活、组胺释放和细胞因子产生。FCERI 激活还触发 PLCγ的磷酸化，在膜定位后水解 PIP2 形成 IP3 和 1,2-二酰基甘油（DAG）-第二信使，分别释放内源性钙离子并激活 PKC。脱颗粒或组胺释放随后由 PLCγ和蛋白激酶 C（PKC）的激活以及钙离子（Ca2+）的动员所触发。受体聚集还导致接头蛋白 NTAL/LAT2 的磷酸化，随后招募 GAB2。PI3K 与磷酸化的 GAB2 结合并催化膜内形成 PIP3，这吸引了许多 PH 结构域蛋白如 BTK、PLCγ、AKT 和 PDK。PI3K 介导的 AKT 激活调节肥大细胞的增殖、发育和生存（Gu 等人 2001）。
英文描述
Fc epsilon receptor (FCERI) signaling Mast cells (MC) are distributed in tissues throughout the human body and have long been recognized as key cells of type I hypersensitivity reactions. They also play important roles in inflammatory and immediate allergic reactions. Activation through FCERI-bound antigen-specific IgE causes release of potent inflammatory mediators, such as histamine, proteases, chemotactic factors, cytokines and metabolites of arachidonic acid that act on the vasculature, smooth muscle, connective tissue, mucous glands and inflammatory cells (Borish & Joseph 1992, Amin 2012, Metcalfe et al. 1993). FCERI is a multimeric cell-surface receptor that binds the Fc fragment of IgE with high affinity. On mast cells and basophils FCERI exists as a tetrameric complex consisting of one alpha-chain, one beta-chain, and two disulfide-bonded gamma-chains, and on dendritic cells, Langerhans cells, macrophages, and eosinophils it exists as a trimeric complex with one alpha-chain and two disulfide-bonded gamma-chains (Wu 2011, Kraft & Kinet 2007). FCERI signaling in mast cells includes a network of signaling molecules and adaptor proteins. These molecules coordinate ultimately leading to effects on degranulation, eicosanoid production, and cytokine and chemokine production and cell migration and adhesion, growth and survival.
The first step in FCERI signaling is the phosphorylation of the tyrosine residues in the ITAM of both the beta and the gamma subunits of the FCERI by LYN, which is bound to the FCERI beta-chain. The phosphorylated ITAM then recruits the protein tyrosine kinase SYK (spleen tyrosine kinase) which then phosphorylates the adaptor protein LAT. Phosphorylated LAT (linker for activation of T cells) acts as a scaffolding protein and recruits other cytosolic adaptor molecules GRB2 (growth-factor-receptor-bound protein 2), GADS (GRB2-related adaptor protein), SHC (SRC homology 2 (SH2)-domain-containing transforming protein C) and SLP76 (SH2-domain-containing leukocyte protein of 76 kDa), as well as the exchange factors and adaptor molecules VAV and SOS (son of sevenless homologue), and the signalling enzyme phospholipase C gamma1 (PLC-gamma1). Tyrosoine phosphorylation of enzymes and adaptors, including VAV, SHC GRB2 and SOS stimulate small GTPases such as RAC, RAS and RAF. These pathways lead to activation of the ERK, JNK and p38 MAP kinases, histamine release and cytokine production. FCERI activation also triggers the phosphorylation of PLC-gamma which upon membrane localisation hydrolyse PIP2 to form IP3 and 1,2-diacylglycerol (DAG) - second messengers that release Ca2+ from internal stores and activate PKC, respectively. Degranulation or histamine release follows the activation of PLC-gamma and protein kinase C (PKC) and the increased mobilization of calcium (Ca2+). Receptor aggregation also results in the phosphorylation of adaptor protein NTAL/LAT2 which then recruits GAB2. PI3K associates with phosphorylated GAB2 and catalyses the formation of PIP3 in the membrane, which attracts many PH domain proteins like BTK, PLC-gamma, AKT and PDK. PI3K mediated activation of AKT then regulate the mast cell proliferation, development and survival (Gu et al. 2001).
The first step in FCERI signaling is the phosphorylation of the tyrosine residues in the ITAM of both the beta and the gamma subunits of the FCERI by LYN, which is bound to the FCERI beta-chain. The phosphorylated ITAM then recruits the protein tyrosine kinase SYK (spleen tyrosine kinase) which then phosphorylates the adaptor protein LAT. Phosphorylated LAT (linker for activation of T cells) acts as a scaffolding protein and recruits other cytosolic adaptor molecules GRB2 (growth-factor-receptor-bound protein 2), GADS (GRB2-related adaptor protein), SHC (SRC homology 2 (SH2)-domain-containing transforming protein C) and SLP76 (SH2-domain-containing leukocyte protein of 76 kDa), as well as the exchange factors and adaptor molecules VAV and SOS (son of sevenless homologue), and the signalling enzyme phospholipase C gamma1 (PLC-gamma1). Tyrosoine phosphorylation of enzymes and adaptors, including VAV, SHC GRB2 and SOS stimulate small GTPases such as RAC, RAS and RAF. These pathways lead to activation of the ERK, JNK and p38 MAP kinases, histamine release and cytokine production. FCERI activation also triggers the phosphorylation of PLC-gamma which upon membrane localisation hydrolyse PIP2 to form IP3 and 1,2-diacylglycerol (DAG) - second messengers that release Ca2+ from internal stores and activate PKC, respectively. Degranulation or histamine release follows the activation of PLC-gamma and protein kinase C (PKC) and the increased mobilization of calcium (Ca2+). Receptor aggregation also results in the phosphorylation of adaptor protein NTAL/LAT2 which then recruits GAB2. PI3K associates with phosphorylated GAB2 and catalyses the formation of PIP3 in the membrane, which attracts many PH domain proteins like BTK, PLC-gamma, AKT and PDK. PI3K mediated activation of AKT then regulate the mast cell proliferation, development and survival (Gu et al. 2001).
所含基因
16 个基因