Elevation of intracellular cAMP inhibits growth factor-mediated matrix metalloproteinase-9 induction and keratinocyte migration.
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.
McCawley
L J
LJ
Department of Cell Biology, Vanderbilt University, Nashville, TN, USA.
Li
S
S
Benavidez
M
M
Halbleib
J
J
Wattenberg
E V
EV
Hudson
L G
LG
D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D005576:Colforsin; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D000242:Cyclic AMP; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9