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Vol. 58, Issue 1, 145-151, July 2000

Elevation of Intracellular cAMP Inhibits Growth Factor-Mediated Matrix Metalloproteinase-9 Induction and Keratinocyte Migration

Lisa J. McCawley, Shunan Li, Mario Benavidez, Jennifer Halbleib, Elizabeth V. Wattenberg, and Laurie G. Hudson

Department of Cell Biology, Vanderbilt University, Nashville, Tennessee (L.J.M.); Division of Environmental and Occupational Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota (S.L., E.V.W.); and Program in Pharmacology and Toxicology, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico (M.B, J.H., L.G.H.)

Receptor tyrosine kinases are regulators of diverse cellular functions including cell growth, cell survival, differentiation, locomotion, and morphogenesis. Activation of the cAMP-dependent protein kinase A inhibits receptor tyrosine kinase-stimulated growth responses in a number of cell types. In this study, we investigated the consequences of elevated cAMP on growth factor-mediated keratinocyte migration and matrix metalloproteinase (MMP)-9 induction in a human keratinocyte cell line. We found that elevation of intracellular cAMP by forskolin abolishes epidermal growth factor (EGF)- or scatter factor/hepatocyte growth factor-dependent colony dispersion. Concentrations of forskolin that inhibit growth factor-induced motility also eliminate EGF- or scatter factor/hepatocyte growth factor-dependent induction of the 92-kDa gelatinase/MMP-9. In contrast to findings obtained in fibroblasts, elevated intracellular cAMP did not interfere with growth factor-dependent activation of the p42/44 extracellular signal-regulated kinases, indicating that cAMP-dependent inhibition of migration and MMP-9 induction does not occur through perturbation of the extracellular signal-regulated kinases/mitogen-activated protein kinase pathway. However, forskolin effectively inhibited EGF-dependent activation of c-Jun N-terminal kinase and p38, demonstrating that cAMP selectively interferes with a different subset of growth factor-induced mitogen-activated protein kinase signaling cascades than reported previously in fibroblasts. These findings illustrate that EGF concurrently activates multiple mitogen-activated protein kinase signaling cascades in keratinocytes and suggests that each pathway contributes to maximal EGF-dependent migration and proteinase induction.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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