%0 Journal Article
%A Fearnley, Gareth W
%A Odell, Adam F
%A Latham, Antony M
%A Mughal, Nadeem A
%A Bruns, Alexander F
%A Burgoyne, Nicholas J
%A Homer-Vanniasinkam, Shervanthi
%A Zachary, Ian C
%A Hollstein, Monica
%A Wheatcroft, Stephen B
%A Ponnambalam, Sreenivasan
%T VEGF-A isoforms differentially regulate ATF-2-dependent VCAM-1 gene expression and endothelial-leukocyte interactions.
%J Molecular biology of the cell
%V 25
%N 16
%@ 1059-1524
%C Bethesda, Md.
%I American Society for Cell Biology
%M DKFZ-2017-00515
%P 2509 - 2521
%D 2014
%X Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology. VEGF-A stimulates signal transduction pathways that modulate endothelial outputs such as cell migration, proliferation, tubulogenesis, and cell-cell interactions. Multiple VEGF-A isoforms exist, but the biological significance of this is unclear. Here we analyzed VEGF-A isoform-specific stimulation of VCAM-1 gene expression, which controls endothelial-leukocyte interactions, and show that this is dependent on both ERK1/2 and activating transcription factor-2 (ATF-2). VEGF-A isoforms showed differential ERK1/2 and p38 MAPK phosphorylation kinetics. A key feature of VEGF-A isoform-specific ERK1/2 activation and nuclear translocation was increased phosphorylation of ATF-2 on threonine residue 71 (T71). Using reverse genetics, we showed ATF-2 to be functionally required for VEGF-A-stimulated endothelial VCAM-1 gene expression. ATF-2 knockdown blocked VEGF-A-stimulated VCAM-1 expression and endothelial-leukocyte interactions. ATF-2 was also required for other endothelial cell outputs, such as cell migration and tubulogenesis. In contrast, VCAM-1 was essential only for promoting endothelial-leukocyte interactions. This work presents a new paradigm for understanding how soluble growth factor isoforms program complex cellular outputs and responses by modulating signal transduction pathways.
%K ATF2 protein, human (NLM Chemicals)
%K Activating Transcription Factor 2 (NLM Chemicals)
%K Protein Isoforms (NLM Chemicals)
%K VEGFA protein, human (NLM Chemicals)
%K Vascular Cell Adhesion Molecule-1 (NLM Chemicals)
%K Vascular Endothelial Growth Factor A (NLM Chemicals)
%K KDR protein, human (NLM Chemicals)
%K Vascular Endothelial Growth Factor Receptor-2 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:24966171
%2 pmc:PMC4142621
%R 10.1091/mbc.E14-05-0962
%U https://inrepo02.dkfz.de/record/119924