Selective activation of MAPK(erk1/2) by laminin-1 peptide alpha1:Ser(2091)-Arg(2108) regulates macrophage degradative phenotype.
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.
Khan
K M
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Department of Pathology, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021, USA.
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D000595:Amino Acid Sequence; D000818:Animals; D016227:Benzoquinones; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D047029:Lactams, Macrocyclic; D007797:Laminin / Q000494:pharmacology*; D008264:Macrophages / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D007797:Laminin; D010446:Peptide Fragments; D011809:Quinones; D012333:RNA, Messenger; C121346:laminin 1; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010450:Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases