Vascular endothelial cell growth factor activates CRE-binding protein by signaling through the KDR receptor tyrosine kinase

Vascular endothelial cell growth factor (VEGF) plays a crucial role in the development of the cardiovascular system and in promoting angiogenesis asso ciated with physiological and pathological processes. Although a great deal is known of the cytoplasmic signaling pathways activated by VEGF, much les s is known of the mechanisms through which VEGF communicates with the nucle us and alters the activity of transcription factors. Binding of VEGF to the KDR/Flk1 receptor tyrosine kinase induces phosphorylation of the CRE-bindi ng protein (CREB) transcription factor on serine 133 and increases CREB DNA binding and transactivation. p38 MAPK/MSK-1 and protein kinase C/p90RSK pa thways mediate CREB phosphorylation, Confocal microscopy shows that VEGF-in duced phosphorylation of nuclear CREB is blocked by pharmacological inhibit ion 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 r ole in alterations of gene expression important to angiogenesis.