p38 mitogen-activated protein kinase-dependent activation of protein phosphatases 1 and 2A inhibits MEK1 and MEK2 activity and collagenase 1 (MMP-1) gene expression

Degradation of collagenous extracellular matrix by collagenase 1 (also know n as matrix metalloproteinase 1 [MMP-1]) plays a role in the pathogenesis o f various destructive disorders, such as rheumatoid arthritis, chronic ulce rs, and tumor invasion and metastasis. Here, we have investigated the role of distinct mitogen-activated protein kinase (MAPK) pathways in the regulat ion of MMP-1 gene expression. The activation of the extracellular signal-re gulated kinase 1 (ERK1)/ERK2 (designated ERK1,2) pathway by oncogenic Ras, constitutively active Raf-1, or phorbol ester resulted in potent stimulatio n of MMP-1 promoter activity and mRNA expression. In contrast, activation o f stress-activated c-Jun N-terminal kinase and p38 pathways by expression o f constitutively active mutants of Rac, transforming growth factor beta -ac tivated kinase 1 (TAK1), MAPK kinase 3 (MKK3), or MKK6 or by treatment with arsenite or anisomycin did not alone markedly enhance MMP-1 promoter activ ity. Constitutively active MKK6 augmented Raf-1-mediated activation of the MMP-1 promoter, whereas active mutants of TAK1 and MKK3b potently inhibited the stimulatory effect of Raf-1. Activation of p38 MAPK by arsenite also p otently abrogated stimulation of MMP-1 gene expression by constitutively ac tive Pas and Raf-1 and by phorbol ester. Specific activation of p38 alpha b y adenovirus-delivered constitutively active MKK3b resulted in potent inhib ition of the activity of ERK1,2 and its upstream activator MEK1,2. Furtherm ore, arsenite prevented phorbol ester-induced phosphorylation of ERK1,2 kin ase-MEK1,2, and this effect was dependent on p38-mediated activation of pro tein phosphatase 1 (PP1) and PP2A, These results provide evidence that acti vation of signaling cascade MKK3-MKK3b-->p38 alpha blocks the ERK1,2 pathwa y at the level of MEK1,2 via PP1-PP2A and inhibits the activation of MMP-1 gene expression.