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The dioxin receptor controls β1 integrin activation in fibroblasts through a Cbp-Csk-Src pathway

机译:二恶英受体通过Cbp-Csk-Src途径控制成纤维细胞中β1整合素的活化

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Recent studies have suggested a regulatory role for the dioxin receptor (AhR) in cell adhesion and migration. Following our previous work, we report here that the C-terminal Src kinase-binding protein (Cbp) signaling pathway controls β1 integrin activation and that this mechanism is AhR dependent. T-FGM AhR-/- fibroblasts displayed higher integrin β1 activation, revealed by the increased binding of the activation reporter 9EG7 anti-β1 mAb and of a soluble fibronectin fragment, as well as by enhanced talin-β1 association. AhR-/- fibroblasts also showed increased fibronectin secretion and impaired directional migration. Notably, interfering Cbp expression in AhR-/- fibroblasts reduced β1 integrin activation, improved cell migration and rescued wild-type cell morphology. Cbp over-expression in T-FGM AhR-/- cells enhanced the formation of inhibitory Csk-Cbp complexes which in turn reduced c-Src p-Tyr~(416) activation and focal adhesion kinase (FAK) phosphorylation at the c-Src-responsive residues p-Tyr~(576) and p-Tyr~(577). The c-Src target and migration-related protein Cav1 was also hypophosphorylated at p-Tyr~(14) in AhR-/- cells, and such effect was rescued by down-modulating Cbp levels. Thus, AhR regulates fibroblast migration by modulating β1 integrin activation via Cbp-dependent, Src-mediated signaling.
机译:最近的研究表明,二恶英受体(AhR)在细胞粘附和迁移中起调节作用。在我们之前的工作之后,我们在这里报告C末端Src激酶结合蛋白(Cbp)信号通路控制β1整联蛋白激活,并且该机制是AhR依赖性的。 T-FGM AhR-/-成纤维细胞显示出更高的整联蛋白β1激活,这是由于激活报告基因9EG7抗β1mAb和可溶性纤连蛋白片段的结合增加,以及塔林-β1缔合增强所致。 AhR-/-成纤维细胞还显示出纤连蛋白分泌增加和定向迁移受损。值得注意的是,AhR-/-成纤维细胞中干扰Cbp的表达减少了β1整联蛋白的活化,改善了细胞迁移并挽救了野生型细胞的形态。 T-FGM AhR-/-细胞中Cbp的过表达增强了抑制性Csk-Cbp复合物的形成,从而降低了c-Src p-Tyr〜(416)激活和c-Src处的粘着斑激酶(FAK)磷酸化-响应性残基p-Tyr_(576)和p-Tyr_(577)。 c-Src靶标和与迁移有关的蛋白Cav1在AhR-/-细胞的p-Tyr〜(14)处也被磷酸化,这种作用通过下调Cbp水平得以挽救。因此,AhR通过依赖于Cbp的Src介导的信号传导调节β1整联蛋白激活来调节成纤维细胞迁移。

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