García-Cardeña G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa W C
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Nature. 1998 Apr 23;392(6678):821-4. doi: 10.1038/33934.
Heat-shock protein 90 (Hsp90) coordinates the trafficking and regulation of diverse signalling proteins, but its precise role in regulating specific cellular targets is not known. Here we show that Hsp90 associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production of nitric oxide, namely vascular endothelial growth factor, histamine and fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS. Inhibition of signalling through Hsp90 attenuates both agonist-stimulated production of nitric oxide and endothelium-dependent relaxation of isolated blood vessels. Our results indicate that Hsp90 facilitates signalling mediated by growth-factor, G-protein and mechanotransduction pathways that lead to the activation of eNOS. These observations indicate that in addition to its role as a molecular chaperone involved in protein folding and maturation, Hsp90 may also be recruited to cellular targets depending on the activation state of the cell.
热休克蛋白90（Hsp90）协调多种信号蛋白的运输和调节，但其在调节特定细胞靶点中的精确作用尚不清楚。在此我们表明，Hsp90与内皮型一氧化氮合酶（eNOS）相关联，并被刺激一氧化氮产生的激动剂迅速招募到eNOS复合物中，这些激动剂包括血管内皮生长因子、组胺和流体剪切应力。此外，Hsp90与eNOS的结合增强了eNOS的激活。通过Hsp90抑制信号传导会减弱激动剂刺激的一氧化氮产生以及离体血管的内皮依赖性舒张。我们的结果表明，Hsp90促进由生长因子、G蛋白和机械转导途径介导的信号传导，这些途径导致eNOS的激活。这些观察结果表明，除了作为参与蛋白质折叠和成熟的分子伴侣的作用外，Hsp90还可能根据细胞的激活状态被招募到细胞靶点。
