Selective activation of MAPK(erk1/2) by laminin-1 peptide alpha1:Ser(2091)-Arg(2108) regulates macrophage degradative phenotype.

TitleSelective activation of MAPK(erk1/2) by laminin-1 peptide alpha1:Ser(2091)-Arg(2108) regulates macrophage degradative phenotype.
Publication TypeJournal Article
Year of Publication2000
AuthorsKhan KM, Falcone DJ
JournalJ Biol Chem
Date Published2000 Feb 11
KeywordsAmino Acid Sequence, Animals, Benzoquinones, Cell Line, Endopeptidases, Enzyme Activation, Enzyme Inhibitors, Extracellular Matrix, Gene Expression Regulation, Lactams, Macrocyclic, Laminin, Macrophages, Metalloendopeptidases, Mice, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Peptide Fragments, Phosphorylation, Protein Kinase C, Protein-Tyrosine Kinases, Quinones, Rifabutin, RNA, Messenger, Urokinase-Type Plasminogen Activator

Components of the extracellular matrix contain cryptic domains, which are exposed by proteolysis and elicit biological responses distinct from intact molecules. The disparate cellular response to extracellular matrix fragments and parent intact molecules suggests differential recognition and signaling pathways. In experiments reported here, we demonstrate that urokinase and matrix metalloproteinase-9 expression by RAW264.7 macrophages is stimulated by a synthetic laminin peptide derived from the alpha1-chain (SRARKQAASIKVAVSADR), whereas intact laminin-1 has no effect on proteinase expression by macrophages. Incubation of macrophages with alpha1:SRARKQAASIKVAVSADR stimulates tyrosine phosphorylation of several proteins including mitogen-activated protein kinase (MAPK)(erk1/2). In contrast, neither intact laminin-1 nor the beta1-chain peptide CDPGYIGSR stimulated protein tyrosine phosphorylation in these cells. Inhibition of tyrosine kinases or protein kinase C blocked alpha1-chain peptide-induced phosphorylation of MAPK(erk1/2) and the up-regulation of steady state levels of urokinase mRNA and matrix metalloproteinase-9 activity. A MAPK kinase inhibitor blocked alpha1-chain-induced phosphorylation of MAPK(erk1/2) and the induction of proteinase expression. 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 alpha1:SRARKQAASIKVAVSADR, but not intact laminin-1, triggers protein kinase C-dependent activation of MAPK(erk1/2), leading to the up-regulation of proteinase expression.

Alternate JournalJ Biol Chem
PubMed ID10660623
Grant ListR01-HL40819 / HL / NHLBI NIH HHS / United States
T32-HL07432 / HL / NHLBI NIH HHS / United States
Related Faculty: 
Domenick J. Falcone, Ph.D.

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