The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn
The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn
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DOI：
10.1182/blood-2007-01-066092
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发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Kawakami, Toshiaki
中科院分区：
文献类型：
--
作者：
Hong, Hong;Kitaura, Jiro;Kawakami, Toshiaki
IgE/抗原依赖性肥大细胞活化在速发型超敏反应和其他过敏反应中起核心作用。Src家族酪氨酸激酶（SFK）林恩通过高亲和力IgE受体（Fc IgE RI）的交联而活化。活化的林恩使Fc γ RI亚基β和γ磷酸化，导致随后各种信号传导途径的活化。林恩还通过激活负调控分子发挥负调控功能。另一种SFK，Fyn，也通过诱导Gab 2依赖性微管的形成来促进肥大细胞脱粒。在这里，我们表明，第三SFK，HCK，在肥大细胞活化中起着至关重要的作用。在Fc γ RI刺激的hck（-/-）肥大细胞中，脱粒和细胞因子产生减少。减少的脱粒可以通过Gab 2磷酸化和微管形成的缺陷来解释。重要的是，林恩活性在hck（-/-）细胞中升高，导致几种负调节因子的磷酸化增加。然而，在hck（-/-）肥大细胞中，诸如Syk、Btk、JNK、p38、Akt和NF-κ B的活化的正调节事件显著减少。对林恩（-/-）hck（-/-）、林恩（-/-）Fc epsilon-RI beta（-/-）和hck（-/-）Fc epsilon-RI beta（-/-）细胞的分析表明，Hck通过依赖于Lynn和不依赖于Lynn的机制发挥这些功能。因此，本研究揭示了SFK成员之间的分级调节，以微调肥大细胞活化。
IgE/antigen-dependent mast cell activation plays a central role in immediate hypersensitivity and other allergic reactions. The Src family tyrosine kinase (SFK) Lyn is activated by the cross-linking of high-affinity IgE receptors (Fc epsilon RI). Activated Lyn phosphorylates the Fc epsilon RI subunits, beta and gamma, leading to subsequent activation of various signaling pathways. Lyn also plays a negative regulatory function by activating negative regulatory molecules. Another SFK, Fyn, also contributes to mast cell degranulation by inducing Gab2-dependent microtubule formation. Here we show that a third SFK, Hck, plays a critical role in mast cell activation. Degranulation and cytokine production are reduced in Fc epsilon RI-stimulated hck(-/-) mast cells. The reduced degranulation can be accounted for by defects in Gab2 phosphorylation and microtubule formation. Importantly, Lyn activity is elevated in hck(-/-) cells, leading to increased phosphorylation of several negative regulators. However, positive regulatory events, such as activation of Syk, Btk, JNK, p38, Akt, and NF-kappa B, are substantially reduced in hck(-/-) mast cells. Analysis of lyn(-/-)hck(-/-), lyn(-/-)Fc epsilon-RI beta(-/-), and hck(-/-)Fc epsilon RI beta(-/-) cells shows that Hck exerts these functions via both Lyn-dependent and Lyn-independent mechanisms. Thus, this study has revealed a hierarchical regulation among SFK members to fine-tune mast cell activation.