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
.