c-jun amino-terminal kinase and mitogen activated protein kinase 1/2 mediate hepatocyte growth factor-induced migration of brain endothelial cells
| Autor: | H. Anne Leaver, Ayoola Bamisaiye, Gausal A. Khan, Maria Teresa Rizzo, Philip Bidwell, Stephen Rush |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
MAPK/ERK pathway
MAP Kinase Signaling System Angiogenesis MAP Kinase Kinase 2 MAP Kinase Kinase 1 Biology Models Biological Cell Movement Proto-Oncogene Proteins medicine Humans Enzyme Inhibitors Phosphorylation Extracellular Signal-Regulated MAP Kinases Protein kinase B Cells Cultured c-Mer Tyrosine Kinase Hepatocyte Growth Factor JNK Mitogen-Activated Protein Kinases Brain Endothelial Cells Receptor Protein-Tyrosine Kinases Cell Biology Cell biology Enzyme Activation Proto-Oncogene Proteins c-raf Focal Adhesion Kinase 2 src-Family Kinases Mitogen-activated protein kinase Cancer research biology.protein Hepatocyte growth factor Signal transduction Signal Transduction medicine.drug Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Experimental Cell Research. 313:121-132 |
| ISSN: | 0014-4827 |
| DOI: | 10.1016/j.yexcr.2006.09.018 |
| Popis: | Hepatocyte growth factor (HGF) influences several components of the angiogenic response, including endothelial cell migration. While recent studies indicate a crucial role of HGF in brain angiogenesis, the signaling pathways that regulate brain endothelial cell migration by HGF remain uncharacterized. Herein, we report that HGF stimulated human brain microvascular endothelial cell (HBMEC) migration in a dose- and time-dependent manner. Challenge of HBMECs with HGF activated the c-jun amino-terminal kinase (JNK), increased phosphorylation of the proline-rich tyrosine kinase 2 (Pyk-2) at Tyr402 and activated c-Src. Inhibition of JNK by SP600125 or expression of a dominant negative JNK1 construct abrogated the migratory response of HBMECs to HGF. Treatment of HBMECs with the Src inhibitor PP2 markedly decreased HGF-stimulated JNK activation and migration to HGF. Moreover, expression of a mutant Pyk-2 construct prevented HGF-induced Pyk-2 phosphorylation at Tyr402 and stimulation of HBMEC migration. Next, we examined activation of the extracellular signal regulated kinase (ERK) pathway. Stimulation of HBMECs by HGF led to rapid activation of ERK1/2, phosphorylation of Raf-1 at Ser338 and Tyr340/341 and MEK1/2 at Ser222. Moreover, inhibition of ERK activation by UO126 and PD98059 markedly decreased HGF-stimulated HBMEC migration. HGF also activated AKT, while inhibition of AKT by LY294002 induced a modest decrease of HGF-induced HBMEC migration. These results highlight a model whereby JNK and ERK play a critical role in regulation of brain endothelial cell migration by HGF. |
| Databáze: | OpenAIRE |
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