Sustained activation of the mitogen-activated protein kinase pathway. A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration

• Published in: The Journal of biological chemistry Vol. 274; no. 7; pp. 4347 - 4353
• Main Authors: McCawley, L J, Li, S, Wattenberg, E V, Hudson, L G
• Format: Journal Article
• Language: English
• Published: United States 12.02.1999
• Subjects: Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Movement; Collagenases - biosynthesis; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Enzyme Induction; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 1; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Saccharomyces cerevisiae Proteins; Substrate Specificity; Tumor Cells, Cultured
• ISSN: 0021-9258
• DOI: 10.1074/jbc.274.7.4347

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.