SDF-1α stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration

Abstract

The chemokine stromal cell-derived factor-1␣ (SDF-1␣) 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␣-induced endothelial cell function. In this report, we describe the identification of an intricate SDF-1␣-induced signaling cascade that involves endothelial nitric oxide synthase (eNOS), JNK3, and MAPK phosphatase 7 (MKP7). We demonstrate that the SDF-1␣-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␣-induced endothelial cell migration. In addition, the discovery of this interactive network of pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.

Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner

“…Although it has been reported that ADM promotes angiogenesis in vitro through the activation of some signaling pathways (38), the nature of TAM-derived ADM and its mechanism involved in angiogenesis and tumor growth merit further studies. The activation of eNOS in endothelial cells is an important intracellular signaling event for angiogenesis (40)(41)(42). VEGF, similar to ADM, is a proangiogenic factor, which enhances angiogenesis through the activation of eNOS signaling pathway (43).…”

A Quick Fix?

“…11 This pathway is regulated by eNOS at several levels: CXCR4 signaling is eNOS dependent, and upregulation of matrix metalloproteinase-9 and release of soluble kit ligand are impaired in eNOSknockout mice. 12,13 Interestingly, a single dose of AMD injected under steady-state conditions has been shown to increase circulating levels of SDF-1 and to mobilize hematopoietic progenitors through CXCR4-dependent active secretion of SDF-1 by BM stromal cells.…”

c-Jun N-Terminal Kinases Mediate a Wide Range of Targets in the Metastatic Cascade

“…40,41 Additionally, JNK1 dominant-negative expression suppresses the VEGF-induced proliferation and migration of endothelial cells. 42 JNK3 also promotes endothelial cell migration to facilitate angiogenesis 43 ( Fig. 1).…”

“…Recently, the influence of JNK3 in the circulatory system, including its importance in angiogenesis, was demonstrated. 43 JNK3 is inactivated by promoter methylation in a variety of cancer cell lines, both immune and epithelial in origin. 111 Its function in the prevention of cytokine-mediated apoptosis in pancreatic β-cells has also been noted recently.…”

“…89 If JNKdependent CCL2 production occurs in secondary site cells or in CTCs during metastasis, then this will recruit VEGF-secreting macrophages, leading to endothelial barrier disruption and tumor cell extravasation. Considering the role of JNK3 in endothelial cell mobilization during angiogenesis, 43 it may also contribute to barrier disruption during extravasation (Fig. 2).…”