Zoekopdracht:
faculteit: "FNWI" en publicatiejaar: "2009"
| Auteurs | S. Bellou, M.A. Hink, E. Bagli, E. Panopoulou, P.I.H. Bastiaens, C. Murphy, T. Fotsis | | Titel | VEGF autoregulates its proliferative and migratory ERK1/2 and p38 cascades by enhancing the expression of DUSP1 and DUSP5 phosphatases in endothelial cells |
| Tijdschrift | AM J PHYSIOL-CELL PH |
| Jaargang | 297 |
| Jaar | 2009 |
| Nummer | 6 |
| Pagina's | C1477-C1489 |
| ISSN | 03636143 |
| Faculteit | Faculteit der Natuurwetenschappen, Wiskunde en Informatica |
| Instituut/afd. | FNWI: Swammerdam Institute for Life Sciences (SILS) |
| Samenvatting | Vascular endothelial growth factor (VEGF) is a key angiogenic factor that regulates proliferation and migration of endothelial cells via phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2) and p38, respectively. Here, we demonstrate that VEGF strongly induces the transcription of two dual-specificity phosphatase (DUSP) genes DUSP1 and DUSP5 in endothelial cells. Using fluorescence microscopy, fluorescence lifetime imaging (FLIM), and fluorescence cross-correlation spectroscopy (FCCS), we found that DUSP1/mitogen-activated protein kinases phosphatase-1 (MKP-1) was localized in both the nucleus and cytoplasm of endothelial cells, where it existed in complex with p38 (effective dissociation constant, K-D(eff), values of 294 and 197 nM, respectively), whereas DUSP5 was localized in the nucleus of endothelial cells in complex with ERK1/2 (K-D(eff) 345 nM). VEGF administration affected differentially the K-D(eff) values of the DUSP1/p38 and DUSP5/ERK1/2 complexes. Gain-of-function and lack-of-function approaches revealed that DUSP1/MKP-1 dephosphorylates primarily VEGF-phosphorylated p38, thereby inhibiting endothelial cell migration, whereas DUSP5 dephosphorylates VEGF-phosphorylated ERK1/2 inhibiting proliferation of endothelial cells. Moreover, DUSP5 exhibited considerable nuclear anchoring activity on ERK1/2 in the nucleus, thereby diminishing ERK1/2 export to the cytoplasm decreasing its further availability for activation. |
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