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1 Division of Nephrology,
Proteins
comprising the mitogen-activated protein (MAP) kinase signaling cascade
are activated by a variety of growth factors, but the precise role of
this series of kinase reactions, especially Raf kinase and MAP kinase
kinase (MEK), in vascular smooth muscle (VSM) cell
mitogenesis is not known. In this study, a specific and selective
inhibitor of MEK, PD-98059, was used to examine the role of MEK in DNA
synthesis and Raf-1 activity in VSM cells stimulated with serum as well
as with growth factors encompassing both tyrosine kinase and G
protein-coupled receptor classes. Although significant increases in DNA
synthesis are seen after stimulation of VSM cells with either 10%
serum, platelet-derived growth factor (PDGF)-BB, or 
-thrombin,
preincubation of the cells with 50 µM PD-98059 for 1 h inhibits
stimulation by PDGF and thrombin, but not by serum. There is a
dose-dependent inhibition of the mitogenic effect by PD-98059 in all
cases; these results are not affected when PD-98059 is added at times
ranging from 4 h before to 2 h after growth factor addition (times at
which PD-98059 exerts its inhibitory effect). In the presence of
PD-98059, stimulated MAP kinase activity is attenuated when growth
factors are added between 10 min and 4 h, times which correspond to
both early and sustained phases of MAP kinase activity. In addition,
Raf-1 activity is markedly increased by incubation of the cells with
PD-98059, despite attenuation of hyperphosphorylation of this kinase.
Thus growth factors coupled to both tyrosine kinase and G protein
receptors require components of the MAP kinase cascade (MEK
and/or MAP kinase) for VSM cell mitogenesis, whereas serum is
capable of stimulatory effects in the absence of active MEK and MAP
kinase. Furthermore, there exists a functional feedback stimulatory
effect of inhibited MEK on its upstream activator Raf-1 in the case of
serum as well as growth factors coupled to tyrosine kinase and G
protein receptors.
mitogen-activated protein kinase; -thrombin; platelet-derived
growth factor-BB; PD-98059
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