DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation.
DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation.
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DOI：
10.1084/jem.20131926
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发表时间：
2014-06-30
期刊：
影响因子：
--
通讯作者：
Fukui Y
中科院分区：
文献类型：
--
作者：
Ogawa K;Tanaka Y;Uruno T;Duan X;Harada Y;Sanematsu F;Yamamura K;Terasawa M;Nishikimi A;Côté JF;Fukui Y
DOCK 5是一个关键的信号转导适配器，其协调肥大细胞脱粒所必需的微管网络的重塑。肥大细胞通过分泌储存在分泌颗粒中的化学介质，在诱导过敏反应（一种危及生命的IgE依赖性过敏反应）中发挥关键作用。肥大细胞的脱粒是由高亲和力IgE受体FcεRI的聚集触发的，并涉及微管的动态重排。尽管对FcεRI下游的近端信号了解很多，但控制微管动力学的远端信号事件仍然难以捉摸。在这里，我们报告，DOCK 5，一个非典型的鸟嘌呤核苷酸交换因子（GEF）的Rac，是必不可少的肥大细胞脱粒。因此，我们发现DOCK 5缺陷小鼠表现出对全身和皮肤过敏反应的抵抗力。令人惊讶的是，D 0 CK 5的Rac GEF活性对于肥大细胞脱粒不是必需的。相反，DOCK 5与Nck 2和Akt相关，通过磷酸化和GSK 3 β失活来调节微管动力学。当DOCK 5-Nck 2-Akt相互作用被破坏时，微管形成和脱粒反应严重受损。因此，我们的研究结果确定DOCK 5作为一个关键的信号转导适配器，协调重塑的微管网络至关重要的肥大细胞脱粒。
DOCK5 is a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation. Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, FcεRI, and involves dynamic rearrangement of microtubules. Although much is known about proximal signals downstream of FcεRI, the distal signaling events controlling microtubule dynamics remain elusive. Here we report that DOCK5, an atypical guanine nucleotide exchange factor (GEF) for Rac, is essential for mast cell degranulation. As such, we found that DOCK5-deficient mice exhibit resistance to systemic and cutaneous anaphylaxis. The Rac GEF activity of DOCK5 is surprisingly not required for mast cell degranulation. Instead, DOCK5 associated with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β. When DOCK5–Nck2–Akt interactions were disrupted, microtubule formation and degranulation response were severely impaired. Our results thus identify DOCK5 as a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation.
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DOI：
10.1084/jem.20091776
发表时间：
2010-04-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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影响因子：
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作者：
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