Publication Date:
2003-07-05
Description:
Raf kinases have been linked to endothelial cell survival. Here, we show that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) differentially activate Raf, resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature. bFGF activated Raf-1 via p21-activated protein kinase-1 (PAK-1) phosphorylation of serines 338 and 339, resulting in Raf-1 mitochondrial translocation and endothelial cell protection from the intrinsic pathway of apoptosis, independent of the mitogen-activated protein kinase kinase-1 (MEK1). In contrast, VEGF activated Raf-1 via Src kinase, leading to phosphorylation of tyrosines 340 and 341 and MEK1-dependent protection from extrinsic-mediated apoptosis. These findings implicate Raf-1 as a pivotal regulator of endothelial cell survival during angiogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alavi, Alireza -- Hood, John D -- Frausto, Ricardo -- Stupack, Dwayne G -- Cheresh, David A -- CA45726/CA/NCI NIH HHS/ -- CA50286/CA/NCI NIH HHS/ -- CA75924/CA/NCI NIH HHS/ -- P01 CA78045/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2003 Jul 4;301(5629):94-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12843393" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Apoptosis
;
Cell Survival
;
Cells, Cultured
;
Chick Embryo
;
Endothelial Growth Factors/pharmacology
;
Endothelium, Vascular/*cytology/drug effects
;
Enzyme Activation
;
Enzyme Inhibitors/pharmacology
;
Fibroblast Growth Factor 2/pharmacology
;
Flavonoids/pharmacology
;
Humans
;
Intercellular Signaling Peptides and Proteins/pharmacology
;
Lymphokines/pharmacology
;
MAP Kinase Kinase 1
;
Mitochondria/metabolism
;
Mitogen-Activated Protein Kinase 1/metabolism
;
Mitogen-Activated Protein Kinase 3
;
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism
;
Mitogen-Activated Protein Kinases/metabolism
;
Neovascularization, Pathologic
;
*Neovascularization, Physiologic/drug effects
;
Phosphorylation
;
Point Mutation
;
Protein Transport
;
Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism
;
Proto-Oncogene Proteins B-raf
;
Proto-Oncogene Proteins c-raf/chemistry/genetics/*metabolism
;
Signal Transduction
;
Umbilical Veins
;
Vascular Endothelial Growth Factor A
;
Vascular Endothelial Growth Factors
;
p21-Activated Kinases
;
src-Family Kinases/antagonists & inhibitors/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
