期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：14
页码：5675-5680
DOI：10.1073/pnas.0809568106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The chemokine stromal cell-derived factor-1{alpha} (SDF-1{alpha}) 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-1{alpha}-induced endothelial cell function. In this report, we describe the identification of an intricate SDF-1{alpha}-induced signaling cascade that involves endothelial nitric oxide synthase (eNOS), JNK3, and MAPK phosphatase 7 (MKP7). We demonstrate that the SDF-1{alpha}-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-1{alpha}-induced endothelial cell migration. In addition, the discovery of this interactive network of pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.
