Interleukin-1 Receptor-Associated Kinase-1 (IRAK-1) functionally associates with PKCepsilon and VASP in the regulation of macrophage migration.
Interleukin-1 Receptor-Associated Kinase-1 (IRAK-1) functionally associates with PKCepsilon and VASP in the regulation of macrophage migration.
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DOI：
10.1016/j.molimm.2009.12.004
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发表时间：
2010-03
影响因子：
3.6
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Gan L;Li L
巨噬细胞的迁移是由复杂的细胞信号传递过程和细胞骨架重排介导的。特别是最近的研究进展表明，天然免疫信号传递过程在巨噬细胞迁移的调节中起着关键作用。在这份报告中，我们提供了证据表明，一种关键的天然免疫信号激酶，白介素1受体相关激酶-1(IRAK-1)参与了巨噬细胞迁移的关键调节因子。与野生型巨噬细胞相比，佛波酯诱导的巨噬细胞迁移在IRAK-1−/−巨噬细胞中显著减弱。我们从机制上证明了IRAK-1在蛋白激酶Cε下游和ENA/Vasp家族成员Vasp的上游起作用。IRAK-1与PKCε和Vasp形成紧密的复合体，参与PMA诱导的Vasp的磷酸化。值得注意的是，IRAK-1的N末端含有一个新的EVH1结构域结合基序(L167WPPPP)，负责其与Vasp的相互作用。突变体IRAK-1(L167A/W168A)不能与Vasp结合。我们的发现为调节巨噬细胞迁移的分子信号过程提供了一个新的方面。
Macrophage migration is mediated by complex cellular signaling processes and cytoskeleton re-arrangement. In particular, recent advances indicate that the innate immunity signaling process plays a key role in the regulation of macrophage migration. In this report, we have provided evidence demonstrating the involvement of a key innate immunity signaling kinase, Interleukin-1 Receptor-Associated Kinase-1(IRAK-1) as a critical modulator of macrophage migration. Macrophage migration induced by phorbol 12-myristate 13-acetate (PMA) is significantly attenuated in IRAK-1−/− macrophages as compared to wild type macrophages. Mechanistically, we demonstrated that IRAK-1 works downstream of PKCε and upstream of VASP, a member of Ena/VASP family proteins. IRAK-1 forms a close complex with PKCε as well as VASP, and participates in PMA-induced phosphorylation of VASP. Notably, IRAK-1 contains a novel EVH1 domain binding motif (L167WPPPP) within its N-terminus, which is responsible for its interaction with VASP. The mutant IRAK-1 (L167A/W168A) fails to associate with VASP. Our findings provide a novel facet regarding the molecular signaling process regulating macrophage migration.
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