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

Activation of the extracellular signal-regulated kinase (ERK)/mitogen-activ ated protein kinase (MAPK) pathway is required for ligand-dependent regulat ion of numerous cellular functions by receptor tyrosine kinases. We have sh own previously that although many receptor tyrosine kinase ligands are mito gens for keratinocytes, cell migration and induction of the 92-kilodalton g elatinase/matrix metalloproteinase (MMP)-9 are selectively regulated by the epidermal growth factor and scatter factor/hepatocyte growth factor recept ors. In this report we present evidence of an underlying mechanism to accou nt for these observed differences in receptor tyrosine kinase-mediated resp onse. Ligands that are mitogenic, but do not induce MMP-9 or colony dispers ion, transiently activate the p42/p44 ERK/MAP kinases. In contrast, ligands that stimulate MMP-9 induction and colony dispersion induced sustained act ivation of these kinases. The functional significance of sustained MAPK act ivation was demonstrated by inhibition of the MAP kinase kinase MEK1. Disru ption of the prolonged signal by addition of the MEK1 inhibitor PD 98059 up to 4 h after growth factor stimulation substantially impaired ligand-depen dent colony dispersion and MMP-9 induction. These findings support the conc lusion that duration of MAPK activation is an important determinant for cer tain growth factor-mediated functions in keratinocytes.