Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Pi X

PROVIDER: S-EPMC2667036 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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

Pi Xinchun X Wu Yaxu Y Ferguson James E JE Portbury Andrea L AL Patterson Cam C

Proceedings of the National Academy of Sciences of the United States of America 20090323 14

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 phosphatas ...[more]

PMID: 19307591

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Project description:Recent studies have noted the tumor-stroma interaction as an integral part of tumor growth and spread as well as novel avenues for effective treatment. However, the details by which tumor and stroma cells communicate remain poorly understood. Here we show that the migration speed of the non-small-cell lung tumor cell line H838 is significantly increased under the influence of human pulmonary endothelial cells, HPAEC, in a transfilter co-culture system. To elucidate the effect of cell communication on the increased tumor cell migration, we record the H838 transcriptome response after the induction of migration in a hetero- and homogenous co-culture conditions. Gene Set enrichment analysis indicates a migration response of H838 in heterogenous co-culture system. Moreover, computationally transcription factor analysis relates the specific gene expression response to the cytokine-induced up-stream receptor activity and subsequently linking these factors to the upstream receptors via shortest paths across a directed protein-protein interaction network. This analysis predicted TNF- and SDF-1 signaling as well as multiple receptors upstream of Stat3 as putative mediators of the transcriptome response. To close the signaling information path from transcription factors to the possible receptor activation, we determine secretome quantification using a cytokine array. The latter revealed the predicted TNFa, SDF-1a signaling molecules as well as other known migration cytokines, like IL8 and IL6, as possible candidates for increased migration. Addition through the recombinant proteins or respected inhibitions reveal TNFa as well as SDF-1a as an immediate and early-late secreted factors that cause the increase in H838 migration. Interestingly, both factors were not regulated on the gene level of the H838 in heterogenous co-culture conditions, consequential HPAEC produce TNFa and SDF1a as shown by qPCR technique. Concluding, our combined computational and experimental approach revealed a holistic overview on the migration enhancement of lung tumor cells due to endothelial derived factors. Increase in migration is caused by an early TNFa induced inflammation response followed by a SDF-1a activity to sustaining the phenotype of migration. This tumor-endothelial-communication give a new insight for tumor migration.

Dataset Information

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

Publications

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

Similar Datasets

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