Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor-stimulated human epidermal keratinocytes.
Invasion is an essential cellular response that plays an important role in a number of physiological and pathological processes. Matrix metalloproteinase (MMP) production and cell movement are diverse cellular responses integral to the process of invasion. The complexity of the invasive process suggests the necessity of coordinate activation of more than one signaling pathway in order to activate specific factors responsible for regulating these cellular responses. In this report, we demonstrate that cell movement and MMP-9 production are both directly dependent on the activation of endogenous ERK signaling in hepatocyte growth factor (HGF)-or epidermal growth factor (EGF)-stimulated human epidermal keratinocytes. The kinetic profiles of endogenous MEK and ERK activity suggest that prolonged activation of these signal transducers is an underlying mechanism involved in stimulating cell motility and MMP-9 production. In support of this finding, a transient MEK/ERK signal elicited by keratinocyte growth factor (KGF) or insulin-like growth factor-1 (IGF-1) fails to stimulate these invasion-related responses. Specific inhibition of MEK leads to suppression of ERK activation, marked reduction in steady-state levels of c-Fos, and inhibition of cell movement and MMP-9 production. This occurs despite continued activation of JNK and c-Jun signaling in the presence of MEK-specific inhibition. In contrast, when JNK activity is specifically inhibited in HGF-stimulated cells, AP-1 activity is suppressed but cell motility is not affected. This evidence suggests that while ERK and JNK activity are necessary for AP-1 activation, ERK but not JNK is sufficient in stimulating cell motility.
Department of Pathology, The University of Michigan Medical School, Ann Arbor, USA. zeiglerm@umich.edu
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Zeigler
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Chi
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Schmidt
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Varani
D000936:Antigen-Antibody Complex; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism*; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D015971:Gene Expression Regulation, Enzymologic; D006133:Growth Substances / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008156:Luciferases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
D000936:Antigen-Antibody Complex; C496453:FGF7 protein, human; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D018808:Transcription Factor AP-1; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D008156:Luciferases; D011494:Protein Kinases; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; C482125:MAP2K1 protein, human; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D017364:Collagenases; D020780:Matrix Metalloproteinase 9