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

S. Bellou, M. A. Hink, E. Bagli, E. Panopoulou, P. I. Bastiaens, C. Murphy, T. Fotsis

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Abstract

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.
Original languageEnglish
Pages (from-to)C1477-89
JournalAJP: Cell Physiology
Volume297
Publication statusPublished - 2009

Bibliographical note

M1 - 6

Bellou, Sofia Hink, Mark A Bagli, Eleni Panopoulou, Ekaterini Bastiaens, Philippe I H Murphy, Carol Fotsis, Theodore Research Support, Non-U.S. Gov't United States American journal of physiology. Cell physiology Am J Physiol Cell Physiol. 2009 Dec;297(6):C1477-89. Epub 2009 Sep 9.

Keywords

  • Cell Movement/physiology Cell Nucleus/drug effects/metabolism Cell Proliferation Cells, Cultured Drug Interactions Dual Specificity Phosphatase 1/genetics/metabolism Dual-Specificity Phosphatases/genetics/metabolism Endothelial Cells/*cytology/*enzymology Extracellular Signal-Regulated MAP Kinases/*metabolism *Homeostasis Humans Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 3/metabolism Mitogen-Activated Protein Kinase Phosphatases/*metabolism Phosphorylation Tissue Distribution Transcription, Genetic/physiology Umbilical Veins/cytology Up-Regulation/physiology Vascular Endothelial Growth Factor A/*metabolism/pharmacology p38 Mitogen-Activated Protein Kinases/metabolism

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