Abstract
Vascular endothelial cell growth factor (VEGF) plays a crucial role in the development of the cardiovascular system and in promoting angiogenesis associated with physiological and pathological processes. Although a great deal is known of the cytoplasmic signaling pathways activated by VEGF, much less is known of the mechanisms through which VEGF communicates with the nucleus and alters the activity of transcription factors. Binding of VEGF to the KDR/Flk1 receptor tyrosine kinase induces phosphorylation of the CRE-binding protein (CREB) transcription factor on serine 133 and increases CREB DNA binding and transactivation. p38 MAPK/MSK-1 and protein kinase C/p90RSK pathways mediate CREB phosphorylation. Confocal microscopy shows that VEGF-induced phosphorylation of nuclear CREB is blocked by pharmacological inhibition of protein kinase C and p38 mitogen-activated protein kinase signaling. Thus, KDR/Flk1 uses multiple pathways to transmit signals into the nucleus where CREB becomes activated. These results suggest that CREB may play a role in alterations of gene expression important to angiogenesis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activating Transcription Factor 1
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Cell Line
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Cyclic AMP Response Element-Binding Protein / metabolism*
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DNA / metabolism
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DNA-Binding Proteins*
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Electrophoresis, Polyacrylamide Gel
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Endothelial Growth Factors / metabolism
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Endothelial Growth Factors / pharmacology*
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Enzyme Activation
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Humans
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Intracellular Signaling Peptides and Proteins
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Lymphokines / metabolism
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Lymphokines / pharmacology*
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Microscopy, Confocal
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Mitogen-Activated Protein Kinases / metabolism
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Phosphorylation
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Protein Kinase C / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptors, Growth Factor / metabolism*
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Receptors, Vascular Endothelial Growth Factor
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Serine / metabolism
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Signal Transduction*
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Transcription Factors / metabolism
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Transcriptional Activation
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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p38 Mitogen-Activated Protein Kinases
Substances
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Activating Transcription Factor 1
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Cyclic AMP Response Element-Binding Protein
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DNA-Binding Proteins
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Endothelial Growth Factors
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Intracellular Signaling Peptides and Proteins
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Lymphokines
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Receptors, Growth Factor
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Serine
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DNA
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MAP-kinase-activated kinase 2
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MAP-kinase-activated kinase 3
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Protein Serine-Threonine Kinases
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Protein Kinase C
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases