Fibronectin induces macrophage migration through a SFK-FAK/CSF-1R pathway
Fibronectin induces macrophage migration through a SFK-FAK/CSF-1R pathway
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DOI：
10.1080/19336918.2016.1221566
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发表时间：
2017-01-01
影响因子：
3.2
通讯作者：
Rovida, Elisabetta
中科院分区：
文献类型：
--
作者：
Digiacomo, Graziana;Tusa, Ignazia;Rovida, Elisabetta
整合素与细胞外基质（ECM）中的胶原、层粘连蛋白和纤连蛋白（FN）等蛋白质结合后，能够在细胞内传递分子信号，调节细胞的迁移、增殖和分化等生物学功能。除了衔接分子和激酶的激活之外，整联蛋白还反式激活受体酪氨酸激酶（RTK）。特别是，在没有生长因子的情况下，与ECM的粘附可能会促进RTK激活。集落刺激因子-1受体（CSF-1 R）是一种RTK，支持单核细胞/巨噬细胞的存活、增殖和运动，而单核细胞/巨噬细胞是先天免疫和癌症发展的重要组成部分。巨噬细胞与FN的相互作用被认为是宿主防御和创伤修复的重要方面。本研究的目的是研究在巨噬细胞中FN引起的信号和CSF-1 R之间可能的串扰。FN在BAC1.2F5和J774鼠巨噬细胞系和人原代巨噬细胞中诱导迁移。与FN的粘附决定了粘着斑激酶（FAK）和Src家族激酶（SFK）的磷酸化以及SFK/FAK复合物的活化，如桩蛋白磷酸化所证实的。SFK活性是FAK活化和巨噬细胞迁移所必需的。此外，FN诱导的迁移依赖于FAK在鼠巨噬细胞系或人原代巨噬细胞。FN还诱导FAK依赖性/配体非依赖性CSF-1 R磷酸化，以及CSF-1 R和ss 1之间的相互作用。CSF-1 R活性是FN诱导的巨噬细胞迁移所必需的。事实上，CSF-1 R的遗传或药理学抑制阻止了FN诱导的巨噬细胞迁移。我们的研究结果确定了一个新的SFK-FAK/CSF-1 R信号通路，介导FN诱导的巨噬细胞迁移。
Integrins, following binding to proteins of the extracellular matrix (ECM) including collagen, laminin and fibronectin (FN), are able to transducemolecular signals inside the cells and to regulate several biological functions such as migration, proliferation and differentiation. Besides activation of adaptor molecules and kinases, integrins transactivate Receptor Tyrosine Kinases (RTK). In particular, adhesion to the ECM may promote RTK activation in the absence of growth factors. The Colony-Stimulating Factor-1 Receptor (CSF-1R) is a RTK that supports the survival, proliferation, and motility ofmonocytes/macrophages, which are essential components of innate immunity and cancer development. Macrophage interaction with FN is recognized as an important aspect of host defense and wound repair. The aim of the present study was to investigate on a possible cross-talk between FN-elicited signals and CSF-1R in macrophages. FN induced migration in BAC1.2F5 and J774 murine macrophage cell lines and in human primary macrophages. Adhesion to FN determined phosphorylation of the Focal Adhesion Kinase (FAK) and Src Family Kinases (SFK) and activation of the SFK/FAK complex, as witnessed by paxillin phosphorylation. SFK activity was necessary for FAK activation and macrophage migration. Moreover, FN-induced migration was dependent on FAK in either murine macrophage cell lines or human primary macrophages. FN also induced FAK-dependent/ligand-independent CSF-1R phosphorylation, as well as the interaction between CSF-1R and ss 1. CSF-1R activity was necessary for FN-induced macrophage migration. Indeed, genetic or pharmacological inhibition of CSF-1R prevented FN-induced macrophage migration. Our results identified a new SFK-FAK/CSF-1R signaling pathway that mediates FN-induced migration of macrophages.