Pi Xinchun, Wu Yaxu, Ferguson James E, Portbury Andrea L, Patterson Cam
Carolina Cardiovascular Biology Center and Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5675-80. doi: 10.1073/pnas.0809568106. Epub 2009 Mar 23.
The chemokine stromal cell-derived factor-1alpha (SDF-1alpha) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and endothelial cell migration, yet very little is known about the actual signaling events that mediate SDF-1alpha-induced endothelial cell function. In this report, we describe the identification of an intricate SDF-1alpha-induced signaling cascade that involves endothelial nitric oxide synthase (eNOS), JNK3, and MAPK phosphatase 7 (MKP7). We demonstrate that the SDF-1alpha-induced activation of JNK3, critical for endothelial cell migration, depends on the prior activation of eNOS. Specifically, activation of eNOS leads to production of NO and subsequent nitrosylation of MKP7, rendering the phosphatase inactive and unable to inhibit the activation of JNK3. These observations reinforce the importance of nitric oxide and S-nitrosylation in angiogenesis and provide a mechanistic pathway for SDF-1alpha-induced endothelial cell migration. In addition, the discovery of this interactive network of pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.
趋化因子基质细胞衍生因子-1α（SDF-1α）是血管生成中的关键因子。它能够影响诸如管状结构形成和内皮细胞迁移等细胞过程，但对于介导SDF-1α诱导的内皮细胞功能的实际信号转导事件却知之甚少。在本报告中，我们描述了一种复杂的SDF-1α诱导的信号级联反应的鉴定，该级联反应涉及内皮型一氧化氮合酶（eNOS）、JNK3和丝裂原活化蛋白激酶磷酸酶7（MKP7）。我们证明，SDF-1α诱导的对内皮细胞迁移至关重要的JNK3激活依赖于eNOS的预先激活。具体而言，eNOS的激活导致NO的产生以及随后MKP7的亚硝基化，使磷酸酶失活并无法抑制JNK3的激活。这些观察结果强化了一氧化氮和S-亚硝基化在血管生成中的重要性，并为SDF-1α诱导的内皮细胞迁移提供了一个机制途径。此外，这一相互作用的信号通路网络的发现为血管生成依赖性疾病提供了新的、意想不到的治疗靶点。
