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首页> 外文期刊>Journal of Cellular Physiology >Regulation of endothelial barrier function by TGF-beta type I receptor ALK5: potential role of contractile mechanisms and heat shock protein 90.
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Regulation of endothelial barrier function by TGF-beta type I receptor ALK5: potential role of contractile mechanisms and heat shock protein 90.

机译:调节内皮屏障功能I型受体ALK5:潜在的作用收缩机制和热休克蛋白90。

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摘要

Multifunctional cytokine transforming growth factor-beta (TGF-beta1) plays a critical role in the pathogenesis of acute lung inflammation by controlling endothelial monolayer permeability. TGF-beta1 regulates endothelial cell (EC) functions via two distinct receptors, activin receptor-like kinase 1 (ALK1) and activin receptor-like kinase 5 (ALK5). The precise roles of ALK1 and ALK5 in the regulation of TGF-beta1-induced lung endothelium dysfunction remain mostly unknown. We now report that adenoviral infection with constitutively active ALK5 (caALK5), but not caALK1, induces EC retraction and that this receptor predominantly controls EC permeability. We demonstrate that ubiquitinated ALK5 and phosphorylated heat shock protein 27 (phospho-Hsp27) specifically accumulate in the cytoskeleton fraction, which parallels with microtubule collapse, cortical actin disassembly and increased EC permeability. We have found that ALK1 and ALK5 interact with heat shock protein 90 (Hsp90). Moreover, the Hsp90 inhibitor radicicol (RA) prevents accumulation of ubiquitinated caALK5 and phospho-Hsp27 in the cytoskeletal fraction and restore the decreased EC permeability induced by caALK5. We hypothesize that specific translocation of ubiquitinated ALK5 receptor into the cytoskeleton compartment due to its lack of degradation is the mechanism that causes the divergence of caALK1 and caALK5 signaling.
机译:多功能细胞因子改变增长因子(TGF-beta1)发挥了至关重要的作用急性肺部炎症的发病机制控制内皮细胞单层通透性。TGF-beta1调节内皮细胞(EC)功能通过两个不同的受体,激活素受体激酶1 (ALK1)和苯丙酸诺龙受体激酶5 (ALK5)。ALK1和ALK5的规定TGF-beta1-induced肺内皮功能障碍大多不明。adenoviral感染持续活跃ALK5 (caALK5),但不是caALK1,诱发EC收缩,这种受体为主控制EC渗透率。ubiquitinated ALK5和磷酸化热休克蛋白质(phospho-Hsp27 27日)积聚在细胞骨架部分,与微管崩溃,大脑皮层肌动蛋白分解和EC渗透性增加。我们发现ALK1 ALK5与热休克蛋白90(一半)。一半抑制剂radicicol (RA)阻止积累ubiquitinated caALK5和phospho-Hsp27细胞骨架的一部分恢复EC引起渗透率降低caALK5。易位的ubiquitinated ALK5受体细胞骨架间由于缺乏退化的机制造成的散度caALK1 caALK5信号。

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