SDF-1alpha stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration.
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.
Pi
Xinchun
X
Carolina Cardiovascular Biology Center and Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Wu
Yaxu
Y
Ferguson
James E
JE
Portbury
Andrea L
AL
Patterson
Cam
C
D000818:Animals; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology*; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D015398:Signal Transduction
D054377:Chemokine CXCL12; D052250:Nitric Oxide Synthase Type III; D048057:Mitogen-Activated Protein Kinase 10; D054639:Mitogen-Activated Protein Kinase Phosphatases; C439065:DUSP16 protein, human; D054637:Dual-Specificity Phosphatases