TY  - JOUR
AU  - Fearnley, Gareth W
AU  - Odell, Adam F
AU  - Latham, Antony M
AU  - Mughal, Nadeem A
AU  - Bruns, Alexander F
AU  - Burgoyne, Nicholas J
AU  - Homer-Vanniasinkam, Shervanthi
AU  - Zachary, Ian C
AU  - Hollstein, Monica
AU  - Wheatcroft, Stephen B
AU  - Ponnambalam, Sreenivasan
TI  - VEGF-A isoforms differentially regulate ATF-2-dependent VCAM-1 gene expression and endothelial-leukocyte interactions.
JO  - Molecular biology of the cell
VL  - 25
IS  - 16
SN  - 1059-1524
CY  - Bethesda, Md.
PB  - American Society for Cell Biology
M1  - DKFZ-2017-00515
SP  - 2509 - 2521
PY  - 2014
AB  - 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.
KW  - ATF2 protein, human (NLM Chemicals)
KW  - Activating Transcription Factor 2 (NLM Chemicals)
KW  - Protein Isoforms (NLM Chemicals)
KW  - VEGFA protein, human (NLM Chemicals)
KW  - Vascular Cell Adhesion Molecule-1 (NLM Chemicals)
KW  - Vascular Endothelial Growth Factor A (NLM Chemicals)
KW  - KDR protein, human (NLM Chemicals)
KW  - Vascular Endothelial Growth Factor Receptor-2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24966171
C2  - pmc:PMC4142621
DO  - DOI:10.1091/mbc.E14-05-0962
UR  - https://inrepo02.dkfz.de/record/119924
ER  -