Journal Article

DKFZ-2017-00515

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png VEGF-A isoforms differentially regulate ATF-2-dependent VCAM-1 gene expression and endothelial-leukocyte interactions.

Fearnley, G. W. ; Odell, A. F. ; Latham, A. M. ; Mughal, N. A. ; Bruns, A. F. ; Burgoyne, N. J. ; Homer-Vanniasinkam, S. ; Zachary, I. C. ; Hollstein, M.DKFZ* ; Wheatcroft, S. B. ; Ponnambalam, S.

2014
American Society for Cell Biology Bethesda, Md.

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Please use a persistent id in citations: doi:10.1091/mbc.E14-05-0962

Abstract: 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.

Keyword(s): ATF2 protein, human ; Activating Transcription Factor 2 ; Protein Isoforms ; VEGFA protein, human ; Vascular Cell Adhesion Molecule-1 ; Vascular Endothelial Growth Factor A ; KDR protein, human ; Vascular Endothelial Growth Factor Receptor-2

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Contributing Institute(s):

1. Genetische Veränderungen bei der Karzinogenese (C016)

Research Program(s):

1. 313 - Cancer risk factors and prevention (POF3-313) (POF3-313)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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