Elevation of intracellular cAMP inhibits growth factor-mediated matrix metalloproteinase-9 induction and keratinocyte migration

Receptor tyrosine kinases are regulators of diverse cellular functions incl uding cell growth, cell survival, differentiation, locomotion, and morphoge nesis. Activation of the cAMP-dependent protein kinase A inhibits receptor tyrosine kinase-stimulated growth responses in a number of cell types. In t his study, we investigated the consequences of elevated cAMP on growth fact or-mediated keratinocyte migration and matrix metalloproteinase (MMP)-9 ind uction in a human keratinocyte cell line. We found that elevation of intrac ellular cAMP by forskolin abolishes epidermal growth factor (EGF)- or scatt er factor/hepatocyte growth factor-dependent colony dispersion. Concentrati ons 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 o ccur through perturbation of the extracellular signal-regulated kinases/mit ogen-activated protein kinase pathway. However, forskolin effectively inhib ited EGF-dependent activation of c-Jun N-terminal kinase and p38, demonstra ting that cAMP selectively interferes with a different subset of growth fac tor-induced mitogen-activated protein kinase signaling cascades than report ed previously in fibroblasts. These findings illustrate that EGF concurrent ly activates multiple mitogen-activated protein kinase signaling cascades i n keratinocytes and suggests that each pathway contributes to maximal EGF-d ependent migration and proteinase induction.