Selective activation of MAPK(erk1/2) by laminin-1 peptide alpha 1 : Ser(2091)-Arg(2108) regulates macrophage degradative phenotype

Components of the extracellular matrix contain cryptic domains, which are e xposed by proteolysis and elicit biological responses distinct from intact molecules. The disparate cellular response to extracellular matrix fragment s and parent intact molecules suggests differential recognition and signali ng pathways. In experiments reported here, we demonstrate that urokinase an d matrix metalloproteinase-9 expression by RAW264.7 macrophages is stimulat ed by a synthetic laminin peptide derived from the alpha 1-chain (SRARKQAAS IKVAVSADR), whereas intact laminin-l has no effect on proteinase expression by macrophages. Incubation of macrophages with alpha 1:SRARKQAASIKVAVSADR stimulates tyrosine phosphorylation of several proteins including mitogen-a ctivated protein kinase (MAPK)(erk1/2). In contrast, neither intact laminin -1 nor the alpha 1-chain peptide CDPGY-IGSR stimulated protein tyrosine pho sphorylation in these cells. Inhibition of tyrosine kinases or protein kina se C blocked alpha 1-chain peptide-induced phosphorylation of MAPK(erk1/2) and the up-regulation of steady state levels of urokinase mRNA and matrix m etalloproteinase-9 activity. A MAPK kinase inhibitor blocked alpha 1-chain- induced phosphorylation of MAPK(erk1/2) and the induction of proteinase exp ression. Intact laminin-1, which was unable to induce macrophage proteinase expression, failed to stimulate the phosphorylation of MAPK(erk1/2). These data demonstrate that incubation of macrophages with alpha 1:SRARKQAASIKVA VSADR, but not intact laminin-1, triggers protein kinase C-dependent activa tion of MAPK(erk1/2), leading to the up-regulation of proteinase expression .