VEGF autoregulates its proliferative and migratory ERK1/2 and p38 cascades by enhancing the expression of DUSP1 and DUSP5 phosphatases in endothelial cells

被引:49
作者
Bellou, Sofia [2 ]
Hink, Mark A. [3 ]
Bagli, Eleni [2 ]
Panopoulou, Ekaterini [1 ]
Bastiaens, Philippe I. H. [3 ]
Murphy, Carol [1 ]
Fotsis, Theodore [1 ,2 ]
机构
[1] FORTH, BRI, Ioannina 45110, Greece
[2] Univ Ioannina, Sch Med, Biol Chem Lab, GR-45110 Ioannina, Greece
[3] Max Planck Inst Mol Physiol, Dept Syst Cell Biol, D-44139 Dortmund, Germany
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2009年 / 297卷 / 06期
关键词
vascular endothelial growth factors; extracellular signal regulated kinase-1/2; p38; dual-specificity phosphatase 1/mitogen-activated protein kinase phosphatase-1; dual-specificity phosphatase-5; MAP KINASE PHOSPHATASE-1; GROWTH-FACTOR; PHYSIOLOGICAL FUNCTIONS; PROTEIN PHOSPHATASES; LIVING CELLS; ACTIVATION; IDENTIFICATION; ANGIOGENESIS; PATHWAYS; MKP-1;
D O I
10.1152/ajpcell.00058.2009
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Bellou S, Hink MA, Bagli E, Panopoulou E, Bastiaens PI, Murphy C, Fotsis T. VEGF autoregulates its proliferative and migratory ERK1/2 and p38 cascades by enhancing the expression of DUSP1 and DUSP5 phosphatases in endothelial cells. Am J Physiol Cell Physiol 297: C1477-C1489, 2009. First published September 9, 2009; doi:10.1152/ajpcell.00058.2009.-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.
引用
收藏
页码:C1477 / C1489
页数:13
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