Open AccessSDF-1α stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration
Author(s) -
Xinchun Pi,
Yaxu Wu,
James E. Ferguson,
Andrea L. Portbury,
Cam Patterson
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0809568106
Subject(s) - angiogenesis , enos , microbiology and biotechnology , endothelial stem cell , stromal cell , nitric oxide synthase type iii , signal transduction , biology , nitric oxide , chemistry , phosphatase , cell migration , cell , nitric oxide synthase , biochemistry , cancer research , phosphorylation , endocrinology , in vitro
The chemokine stromal cell-derived factor-1α (SDF-1α) 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-1α-induced endothelial cell function. In this report, we describe the identification of an intricate SDF-1α-induced signaling cascade that involves endothelial nitric oxide synthase (eNOS), JNK3, and MAPK phosphatase 7 (MKP7). We demonstrate that the SDF-1α-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 andS -nitrosylation in angiogenesis and provide a mechanistic pathway for SDF-1α-induced endothelial cell migration. In addition, the discovery of this interactive network of pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.