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J. Biol. Chem., Vol. 277, Issue 10, 8724-8729, March 8, 2002
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From the Department of Molecular Oncology, Genentech Inc., South
San Francisco, California 94080
Endocrine gland-derived vascular endothelial
growth factor (EG-VEGF) has been recently identified as a mitogen
specific for the endothelium of steroidogenic glands. Here we report a
characterization of the signal transduction of EG-VEGF in a responsive
cell type, bovine adrenal cortex-derived endothelial (ACE) cells.
EG-VEGF led to a time- and dose-dependent phosphorylation
of p44/42 MAPK. This effect was blocked by pretreatment with pertussis
toxin, suggesting that G
Characterization of Endocrine Gland-derived Vascular
Endothelial Growth Factor Signaling in Adrenal Cortex Capillary
Endothelial Cells*
i plays an
important role in mediating EG-VEGF-induced activation of MAPK
signaling. The inhibitor of p44/42 MAPK phosphorylation PD 98059 resulted in suppression of both proliferation and migration in response
to EG-VEGF. EG-VEGF also increased the phosphorylation of Akt in a
phosphatidylinositol 3-kinase-dependent manner.
Consistent with such an effect, EG-VEGF was a potent survival factor
for ACE cells. We also identified endothelial nitric-oxide
synthase as one of the downstream targets of Akt activation.
Phosphorylation of endothelial nitric-oxide synthase in ACE cells was
stimulated by EG-VEGF with a time course correlated to the Akt
phosphorylation. Our data demonstrate that EG-VEGF, possibly through
binding to a G-protein coupled receptor, results in the activation of
MAPK p44/42 and phosphatidylinositol 3-kinase signaling pathways,
leading to proliferation, migration, and survival of responsive
endothelial cells.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Molecular
Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080. Tel.: 650-225-2968; Fax: 650-225-6327; E-mail: nf@gene.com.
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