From the Medical Policlinic/Department of Medicine, Division of
Nephrology, University of Bonn, Germany.
Correspondence to Dirk Bokemeyer, MD, Medizinische Poliklinik, University of Bonn, Wilhelmstr 35-37, 53111 Bonn, Germany. E-mail bokemeyer{at}uni-bonn.de
AbstractMitogen-activated
protein (MAP) kinase cascades are major signaling systems by which
cells transduce extracellular cues into intracellular responses. In
general, MAP kinases are activated by
phosphorylation on tyrosine and threonine residues and
inactivated by dephosphorylation.
Therefore, MAP kinase phosphatase-1 (MKP-1), a dual-specificity protein
tyrosine phosphatase that exhibits catalytic activity toward both
regulatory sites on MAP kinases, is suggested to be responsible for the
downregulation of extracellular signal-regulated kinase (ERK),
stress-activated protein kinase (SAPK), and p38 MAP kinase. In
the present study, we examined the role of these MAP kinases in the
induction of MKP-1 in vascular smooth muscle cells (VSMCs).
Extracellular stimuli such as platelet-derived growth factor
(PDGF), 12-O-tetradecanoylphorbol 13-acetate (TPA),
and angiotensin II, which activated ERK but not
SAPK/p38 MAP kinase, induced a transient induction of MKP-1 mRNA and
its intracellular protein. In addition, PD 098059, an
antagonist of MEK (MAP kinase/ERK kinase), the upstream
kinase of ERK, significantly reduced the PDGF-induced activation of ERK
and potently inhibited the expression of MKP-1 after stimulation with
PDGF, thereby demonstrating the induction of MKP-1 in response to
activation of the ERK signaling cascade. Furthermore, anisomycin, a
potent stimulus of SAPK and p38 MAP kinase, also induced MKP-1 mRNA
expression. This effect of anisomycin was significantly inhibited in
the presence of the p38 MAP kinase antagonist SB 203580.
These data suggest the induction of MKP-1, not only after stimulation
of the cell growthpromoting ERK pathway but also in response to
activation of stress-responsive MAP kinase signaling cascades. We
suggest that this pattern of MKP-1 induction may be a negative feedback
mechanism in the control of MAP kinase activity in VSMCs.
© 1998 American Heart Association, Inc.
Scientific Contributions
Regulation of Mitogen-Activated Protein Kinase Phosphatase-1 in Vascular Smooth Muscle Cells
Key Words: MAP kinase ERK SAPK p38 MAP kinase MKP-1
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