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Vol. 290, Issue 1, 28-37, July 1999
1-Adrenergic Receptor Stimulation of Mitogenesis
in Human Vascular Smooth Muscle Cells: Role of Tyrosine Protein Kinases
and Calcium in Activation of Mitogen-Activated Protein
Kinase1
Department of Medicine, Stanford University School of Medicine, and
Veterans Affairs Palo Alto Health Care System, Palo Alto, California
Signaling pathways of many G protein-coupled receptors overlap with
those of receptor tyrosine kinases. We have found previously that
1-adrenergic receptors stimulate DNA synthesis and cell proliferation in human vascular smooth muscle cells; these effects were
attenuated by the tyrosine protein kinase (TPK) inhibitor genistein and
the mitogen-activated protein kinase (MAPK) antagonist 2-aminopurine.
Experiments were designed to determine if activation of
1 receptors directly stimulated TPKs and MAPKs in human
vascular smooth muscle cells. Norepinephrine stimulated time-
and concentration-dependent tyrosine phosphorylation of multiple
proteins, including p52-, 75-, 85-, 120-, and 145-kDa proteins.
Increased TPK activity was demonstrated in proteins precipitated by an
antiphosphotyrosine antibody, both in autophosphorylation assays and
with a peptide substrate. These effects of norepinephrine were
completely blocked by 1 receptor antagonists. A
membrane-permeable Ca2+ chelator
[1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester], completely blocked
norepinephrine stimulation of phosphorylation of tyrosine proteins,
suggesting that intracellular Ca2+ plays a critical role in
1 receptor stimulation phosphorylation of tyrosine
proteins. Of the tyrosine-phosphorylated proteins, the results suggest
that two of them are PLC
1 and adapter protein Shc. Also,
1 receptor stimulation caused a time-dependent increase in MAPK activity due to increased phosphorylation of
p42/44ERK1/2. The 1 receptor-mediated
activation of MAPK was also attenuated by TPK inhibitors and
intracellular Ca2+ chelator
[1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester]. These results suggest that
phosphorylation of tyrosine proteins and intracellular Ca2+
plays a critical role in 1 receptor-stimulated MAPK
signaling pathways, potentially contributing to increased DNA synthesis and cell proliferation.
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