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Molecular and Cellular Biology, April 2001, p. 2373-2383, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2373-2383.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

p38 Mitogen-Activated Protein Kinase-Dependent Activation of Protein Phosphatases 1 and 2A Inhibits MEK1 and MEK2 Activity and Collagenase 1 (MMP-1) Gene Expression

Jukka Westermarck,1,* Song-Ping Li,1 Tuula Kallunki,2 Jiahuai Han,3 and Veli-Matti Kähäri1,4

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University,1 and Departments of Medical Biochemistry and Dermatology,4 University of Turku, FIN-20520 Turku, Finland; Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark2; and Department of Immunology, Scripps Research Institute, La Jolla, California 921213

Received 19 July 2000/Returned for modification 29 August 2000/Accepted 4 January 2001

Degradation of collagenous extracellular matrix by collagenase 1 (also known as matrix metalloproteinase 1 [MMP-1]) plays a role in the pathogenesis of various destructive disorders, such as rheumatoid arthritis, chronic ulcers, and tumor invasion and metastasis. Here, we have investigated the role of distinct mitogen-activated protein kinase (MAPK) pathways in the regulation of MMP-1 gene expression. The activation of the extracellular signal-regulated kinase 1 (ERK1)/ERK2 (designated ERK1,2) pathway by oncogenic Ras, constitutively active Raf-1, or phorbol ester resulted in potent stimulation of MMP-1 promoter activity and mRNA expression. In contrast, activation of stress-activated c-Jun N-terminal kinase and p38 pathways by expression of constitutively active mutants of Rac, transforming growth factor beta -activated kinase 1 (TAK1), MAPK kinase 3 (MKK3), or MKK6 or by treatment with arsenite or anisomycin did not alone markedly enhance MMP-1 promoter activity. Constitutively active MKK6 augmented Raf-1-mediated activation of the MMP-1 promoter, whereas active mutants of TAK1 and MKK3b potently inhibited the stimulatory effect of Raf-1. Activation of p38 MAPK by arsenite also potently abrogated stimulation of MMP-1 gene expression by constitutively active Ras and Raf-1 and by phorbol ester. Specific activation of p38alpha by adenovirus-delivered constitutively active MKK3b resulted in potent inhibition of the activity of ERK1,2 and its upstream activator MEK1,2. Furthermore, arsenite prevented phorbol ester-induced phosphorylation of ERK1,2 kinase-MEK1,2, and this effect was dependent on p38-mediated activation of protein phosphatase 1 (PP1) and PP2A. These results provide evidence that activation of signaling cascade MKK3-MKK3bright-arrowp38alpha blocks the ERK1,2 pathway at the level of MEK1,2 via PP1-PP2A and inhibits the activation of MMP-1 gene expression.

* Corresponding author. Mailing address: University of Turku, Centre for Biotechnology, Tykistökatu 6B, FIN-20520 Turku, Finland. Phone: 358 2 3338029. Fax: 358 2 3338000. E-mail: jukwes{at}utu.fi.

Molecular and Cellular Biology, April 2001, p. 2373-2383, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2373-2383.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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