Sustained Activation of the Mitogen-activated Protein Kinase Pathway
A MECHANISM UNDERLYING RECEPTOR TYROSINE KINASE SPECIFICITY FOR MATRIX METALLOPROTEINASE-9 INDUCTION AND CELL MIGRATION*
- From the ‡Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, the ¶Division of Environmental and Occupational Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, and the ‖Program in Pharmacology and Toxicology, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131
Abstract
Activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway is required for ligand-dependent regulation of numerous cellular functions by receptor tyrosine kinases. We have shown previously that although many receptor tyrosine kinase ligands are mitogens for keratinocytes, cell migration and induction of the 92-kilodalton gelatinase/matrix metalloproteinase (MMP)-9 are selectively regulated by the epidermal growth factor and scatter factor/hepatocyte growth factor receptors. In this report we present evidence of an underlying mechanism to account for these observed differences in receptor tyrosine kinase-mediated response. Ligands that are mitogenic, but do not induce MMP-9 or colony dispersion, transiently activate the p42/p44 ERK/MAP kinases. In contrast, ligands that stimulate MMP-9 induction and colony dispersion induced sustained activation of these kinases. The functional significance of sustained MAPK activation was demonstrated by inhibition of the MAP kinase kinase MEK1. Disruption of the prolonged signal by addition of the MEK1 inhibitor PD 98059 up to 4 h after growth factor stimulation substantially impaired ligand-dependent colony dispersion and MMP-9 induction. These findings support the conclusion that duration of MAPK activation is an important determinant for certain growth factor-mediated functions in keratinocytes.
Footnotes
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↵* This work was supported in part by National Institutes of Health Grant RO1AR42989 (to L. G. H.), by National Institutes of Health Grant CA72498 (to E. V. W.), and by a Pharmaceutical Research and Manufacturers of America Foundation Research Starter Grant (to E. V. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Supported by National Institutes of Health Training Grant T32GM08061.
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↵** To whom correspondence should be addressed: Program in Pharmacology and Toxicology, UNM Health Sciences Center, 2502 Marble NE, Albuquerque, NM 87131. Tel.: 505-272-2482; Fax: 505-272-6749; E-mail:lghudson{at}unm.edu.
- Abbreviations:
- MAPK
-
mitogen-activated protein kinase
- MAP
-
mitogen-activated protein
- MEK1
-
MAP kinase kinase
- ERK
-
extracellular signal-regulated kinase
- EGF
-
epidermal growth factor
- IGF-1
-
insulin-like growth factor 1
- KGF
-
keratinocyte growth factor
- SF/HGF
-
scatter factor/hepatocyte growth factor
- SCC squamous cell carcinoma
-
JNK/SAPKs, c-Jun N-terminal kinases/stress-activated protein kinases
- MMP
-
matrix metalloproteinase
- DMEM
-
Dulbecco’s modified Eagle’s medium
- BSA
-
bovine serum albumin
- MOPS
-
4-morpholinepropanesulfonic acid
- PAGE
-
polyacrylamide gel electrophoresis.
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- Received August 31, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
