Src-mediated phosphorylation of hsp90 in response to vascular endothelial growth factor (VEGF) is required for VEGF receptor-2 signaling to endothelial NO synthase
Src-mediated phosphorylation of hsp90 in response to vascular endothelial growth factor (VEGF) is required for VEGF receptor-2 signaling to endothelial NO synthase
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DOI：
10.1091/mbc.e07-05-0467
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发表时间：
2007-11-01
影响因子：
3.3
通讯作者：
Gratton, Jean-Philippe
中科院分区：
文献类型：
--
作者：
Duval, Martine;Le Boeuf, Fabrice;Gratton, Jean-Philippe
通过内皮NO合酶（eNOS）活化从内皮细胞释放一氧化氮（NO）是血管内皮生长因子（VEGF）的促血管生成作用的中心。VEGF信号转导至eNOS主要由eNOS的Akt依赖性磷酸化和eNOS与分子伴侣热休克蛋白90 kDa（Hsp 90）的缔合增加介导。在此，我们报道了VEGFR-2激活诱导VEGF受体2（VEGFR-2）相关的Hsp 90 β的酪氨酸磷酸化。响应于VEGF的Hsp 90 β的酪氨酸磷酸化依赖于VEGFR-2的内化和Src激酶活化。此外，我们证明，c-Src直接磷酸化热休克蛋白90酪氨酸300残基，这一事件是必不可少的VEGF刺激的eNOS协会热休克蛋白90，从而NO释放内皮细胞。我们的工作确定了Y300磷酸化热休克蛋白90作为一种新的调节翻译后修饰的伴侣，并证明了其重要性，在促血管生成的行动，即通过调节NO释放的血管内皮细胞的VEGF。
Nitric oxide (NO) release from endothelial cells, via endothelial NO synthase (eNOS) activation, is central to the proangiogenic actions of vascular endothelial growth factor (VEGF). VEGF signaling to eNOS is principally mediated by an Akt-dependent phosphorylation of eNOS and by increased association of eNOS to the molecular chaperone, heat-shock protein 90 kDa (Hsp90). Herein, we report that VEGFR-2 activation induces tyrosine phosphorylation of VEGF receptor 2 (VEGFR-2)-associated Hsp90 beta. Tyrosine phosphorylation of Hsp90 beta in response to VEGF is dependent on internalization of the VEGFR-2 and on Src kinase activation. Furthermore, we demonstrate that c-Src directly phosphorylates Hsp90 on tyrosine 300 residue and that this event is essential for VEGF-stimulated eNOS association to Hsp90 and thus NO release from endothelial cells. Our work identifies Y300 phosphorylation of Hsp90 as a novel regulated posttranslational modification of the chaperone and demonstrates its importance in the proangiogenic actions of VEGF, namely by regulating NO release from endothelial cells.