Ligand binding to macrophage scavenger receptor-A induces urokinase-type plasminogen activator expression by a protein kinase-dependent signaling pathway.
Macrophage scavenger receptor-type A (MSR-A) has been implicated in the transmission of cell signals and the regulation of diverse cellular functions (Falcone, D. J., and Ferenc, M. J. (1988) J. Cell. Physiol. 135, 387-396; Falcone, D. J., McCaffrey, T. A., and Vergilio, J. A. (1991) J. Biol. Chem. 266, 22726-22732; Palkama, T. (1991) Immunology 74, 432-438; Krieger, M., and Herz, J. (1994) Annu. Rev. Biochem. 63, 601-637); however, the signaling mechanisms are unknown. In studies reported here, we demonstrate that binding of both lipoprotein and non-lipoprotein ligands to MSR-A induced protein tyrosine phosphorylation and increased protein kinase C (PKC) activity leading to up-regulated urokinase-type plasminogen activator (uPA) expression. Specifically, the binding of acetylated low density lipoprotein and fucoidan to MSR-A in human THP-1 macrophages triggered tyrosine phosphorylation of many proteins including phospholipase C-gamma1 and phosphatidylinositol-3-OH kinase. Inhibitors of tyrosine kinase dramatically reduced MSR-induced protein tyrosine phosphorylation and PKC activity. Moreover, inhibitors of tyrosine kinase and PKC reduced uPA activity expressed by THP-1 macrophages exposed to MSR-A ligands. The intracellular signaling response for tyrosine phosphorylation following ligand binding was further demonstrated by using the stable MSR-transfected Bowes cells that express surface MSR-A. These findings establish for the first time a signaling pathway induced by ligand binding to MSR-A and suggest a molecular model for the regulation of macrophage uPA expression by specific ligands of the MSR-A.
Hsu
H Y
HY
Department of Medicine, Cornell University Medical College, New York, New York 10021, USA. hyhsu@ym.edu.tu
Hajjar
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DP
Khan
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Falcone
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D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011134:Polysaccharides / Q000494:pharmacology; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000378:metabolism*; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008024:Ligands; D008077:Lipoproteins, LDL; C495139:MSR1 protein, human; D011134:Polysaccharides; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; C032629:acetyl-LDL; D014443:Tyrosine; C007789:fucoidan; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D014568:Urokinase-Type Plasminogen Activator