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Ligand binding to macrophage scavenger receptor-A induces urokinase-type plasminogen activator expression by a
H Y Hsu1, D P Hajjar, K M Khan
1Department of Medicine, Cornell University Medical College, New York, New York 10021, USA. hyhsu@ym.edu.tu
Abstract:
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.
Insights
Ligand binding to Macrophage scavenger receptor-type A (MSR-A) activates intracellular signaling pathways. This leads to increased protein tyrosine phosphorylation and protein kinase C (PKC) activity, up-regulating urokinase-type plasminogen activator (uPA) expression.
Area of Science:
- Cell Biology
- Immunology
- Biochemistry
Background:
- Macrophage scavenger receptor-type A (MSR-A) is involved in cell signaling and regulating cellular functions.
- The specific signaling mechanisms of MSR-A have remained largely unknown.
- Understanding MSR-A signaling is crucial for elucidating macrophage behavior.
Purpose of the Study:
- To investigate the intracellular signaling pathways initiated by MSR-A ligand binding.
- To determine the role of MSR-A in regulating urokinase-type plasminogen activator (uPA) expression.
- To establish a molecular model for MSR-A-mediated signaling.
Main Methods:
- Utilized human THP-1 macrophages and MSR-A-transfected Bowes cells.
- Assessed protein tyrosine phosphorylation and protein kinase C (PKC) activity.
- Employed tyrosine kinase and PKC inhibitors to study signaling pathways.
- Measured urokinase-type plasminogen activator (uPA) expression and activity.
Main Results:
- Binding of lipoprotein and non-lipoprotein ligands to MSR-A induced significant protein tyrosine phosphorylation.
- Key proteins phosphorylated included phospholipase C-gamma1 and phosphatidylinositol-3-OH kinase.
- Inhibition of tyrosine kinase and PKC activity reduced MSR-A-induced protein tyrosine phosphorylation and uPA expression.
- Ligand binding to MSR-A in transfected cells confirmed the intracellular signaling response.
Conclusions:
- Established a novel signaling pathway activated by MSR-A ligand binding.
- Demonstrated that MSR-A signaling involves tyrosine phosphorylation and PKC activation.
- Provided a molecular framework for how MSR-A ligands regulate macrophage uPA expression.