Premium
cAMP‐dependent protein kinase inhibits the mitogenic action of vascular endothelial growth factor and fibroblast growth factor in capillary endothelial cells by blocking Raf activation
Author(s) -
D'Angelo Gisela,
Lee Hsinyu,
Weiner Richard I.
Publication year - 1997
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/(sici)1097-4644(19971201)67:3<353::aid-jcb7>3.0.co;2-v
Subject(s) - mapk/erk pathway , protein kinase a , microbiology and biotechnology , basic fibroblast growth factor , forskolin , mitogen activated protein kinase , vascular endothelial growth factor a , endothelial stem cell , vascular endothelial growth factor , fibroblast growth factor , vascular endothelial growth factor b , cell growth , vascular endothelial growth inhibitor , signal transduction , biology , chemistry , growth factor , endocrinology , kinase , receptor , cancer research , stimulation , biochemistry , in vitro , vegf receptors
Proliferation of endothelial cells is regulated by angiogenic and antiangiogenic factors whose actions are mediated by complex interactions of multiple signaling pathways. Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) stimulate cell proliferation and activate the mitogen‐activated protein kinase (MAPK) cascade in bovine brain capillary endothelial (BBE) cells. We have extended these findings to show that both mitogens activate MAPK via stimulation of Raf‐1. Activation of Raf/MAPK is inhibited by increasing intracellular cAMP levels pharmacologically or via stimulation of endogenously expressed β‐adrenergic receptors. Both VEGF‐ and bFGF‐induced Raf‐1 activity are blocked in the presence of forskolin or 8‐bromo‐cAMP by 80%. The actions of increased cAMP appear to be mediated by cAMP‐dependent protein kinase (PKA), since treatment with H‐89, a the specific inhibitor of PKA, reversed the inhibitory effect of elevated cAMP levels on mitogen‐induced cell proliferation and Raf/MAPK activation. Moreover, elevations in cAMP/PKA activity inhibit mitogen‐induced cell proliferation. These findings demonstrate, in cultured endothelial cells, that the cAMP/PKA signaling pathway is potentially an important physiological inhibitor of mitogen activation of the MAPK cascade and cell proliferation. J. Cell. Biochem. 67:353–366, 1997. © 1997 Wiley‐Liss, Inc.