In rat aortic smooth muscle cells, platelet-derived growth factor (PDGF) stimulated a sustained activation of mitogen-activated protein kinase (MAP kinase) while the response to angiotensin II (AII) was transient. This was due to a relatively greater initial activation of MAP kinase kinase (MEK) and a correspondingly greater residual MEK activity at later time points. Pretreatment of cells with the novel MEK inhibitor PD 098059 reduced MEK activation at 5 min in response to each agonist by a similar proportion (70%); however, at this time point MAP kinase activation in response to PDGF was only marginally affected while the response to AII was substantially reduced. PD 098059 did, however, reduce PDGF-stimulated MEK activity after 30 min and this correlated with a loss in MAP kinase activity and DNA synthesis. Pretreatment with forskolin also caused a similar pattern of inhibition of agonist-stimulated MEK and MAP kinase activity. Only following protein kinase C down-regulation were both AII- and PDGF-stimulated MAP kinase activation substantially reduced and this correlated with the virtual loss of both MEK and c-Raf-1 activity in response to both agents. The differential inhibition of MAP kinase activation by forskolin was not due to specific activation of A-Raf by PDGF; both PDGF and AII stimulated A-Raf kinase and this activity was strongly inhibited by forskolin. These results suggest that the efficacy of MEK activation determines the duration of MAP kinase activation and the susceptibility of MAP kinase activation to inhibition by different agents. The results also argue against the selective activation of A-Raf by PDGF as a mechanism to explain the differences in the kinetics of MAP kinase activity stimulated by AII and PDGF.
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September 1996
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Research Article|
September 01 1996
Efficacy of agonist-stimulated MEK activation determines the susceptibility of mitogen-activated protein (MAP) kinase to inhibition in rat aortic smooth muscle cells
Robin PLEVIN;
Robin PLEVIN
‡
*Department of Physiology and Pharmacology, University of Strathclyde, 204 George St., Glasgow G1 1XW
‡To whom correspondence should be addressed.
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Pamela H SCOTT;
Pamela H SCOTT
*Department of Physiology and Pharmacology, University of Strathclyde, 204 George St., Glasgow G1 1XW
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Casper J. M. ROBINSON;
Casper J. M. ROBINSON
*Department of Physiology and Pharmacology, University of Strathclyde, 204 George St., Glasgow G1 1XW
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Gwyn W. GOULD
Gwyn W. GOULD
†Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K.
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Publisher: Portland Press Ltd
Received:
February 13 1996
Revision Received:
May 01 1996
Accepted:
May 15 1996
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1996
1996
Biochem J (1996) 318 (2): 657–663.
Article history
Received:
February 13 1996
Revision Received:
May 01 1996
Accepted:
May 15 1996
Citation
Robin PLEVIN, Pamela H SCOTT, Casper J. M. ROBINSON, Gwyn W. GOULD; Efficacy of agonist-stimulated MEK activation determines the susceptibility of mitogen-activated protein (MAP) kinase to inhibition in rat aortic smooth muscle cells. Biochem J 1 September 1996; 318 (2): 657–663. doi: https://doi.org/10.1042/bj3180657
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