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Biological aspects of macrophage-stimulating protein (MSP) and its receptor
1Laboratory of Immunobiology, National Cancer Institute, Frederick, MD 21702, USA.
Abstract:
Macrophage-stimulating protein (MSP; also known as HGF-like protein [HGFl]) is a 78 kDa plasma protein that is secreted by the liver into the circulation as single-chain, biologically inactive pro-MSP. The presence of conserved triple disulfide loops (kringles) places pro-MSP in a family of coagulation system serine protease zymogens that are activated by proteolytic cleavage. Although pro-MSP has lost enzymic activity, it has retained the activation mechanism, in that proteolytic cleavage at a single site yields biologically active disulfide-linked alpha beta-chain heterodimeric MSP. The MSP receptor is a transmembrane protein tyrosine kinase. MSP causes phosphorylation of the receptor cytoplasmic domain, association of phosphatidylinositol (PI)-3 kinase with the receptor, and phosphorylation of receptor-bound PI-3 kinase. Inhibition of PI-3 kinase by wortmannin prevents MSP action on cells. MSP stimulates motility of murine resident peritoneal macrophages. However, it does not act on exudate macrophages or blood monocytes, since these earlier maturational stages of the lineage do not express the receptor. MSP also stimulates keratinocyte cell lines, causing either chemotactic responses or increased cell numbers in culture. We suggest that pro-MSP diffuses into local tissue sites, where proteolytic cleavage to MSP results in stimulation of keratinocytes and macrophages. It possibly plays a role in tissue injury or wound healing.
Insights
Macrophage-stimulating protein (MSP) is a liver-secreted protein that activates macrophages and keratinocytes. Its signaling pathway involves a tyrosine kinase receptor and PI-3 kinase, suggesting a role in wound healing.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Macrophage-stimulating protein (MSP), also known as HGF-like protein (HGFL), is a 78 kDa plasma protein.
- Pro-MSP is secreted by the liver as an inactive single chain and belongs to the serine protease zymogen family.
- Pro-MSP is activated by proteolytic cleavage into a disulfide-linked heterodimeric form, retaining its activation mechanism despite loss of enzymatic activity.
Purpose of the Study:
- To investigate the biological activity and signaling pathway of Macrophage-stimulating protein (MSP).
- To determine the cellular targets and potential physiological roles of MSP.
- To elucidate the mechanism of MSP-induced cellular responses.
Main Methods:
- Characterization of pro-MSP activation and its biologically active form.
- Identification and analysis of the MSP receptor, a transmembrane protein tyrosine kinase.
- Investigation of downstream signaling events, including PI-3 kinase association and phosphorylation.
- Assessment of MSP effects on macrophage and keratinocyte cell lines.
Main Results:
- MSP activates a transmembrane protein tyrosine kinase receptor, leading to PI-3 kinase association and phosphorylation.
- MSP stimulates motility and proliferation in murine resident peritoneal macrophages and keratinocyte cell lines.
- Earlier maturational stages of macrophages (exudate macrophages, blood monocytes) do not respond to MSP due to lack of receptor expression.
- Inhibition of PI-3 kinase with wortmannin blocks MSP-induced cellular responses.
Conclusions:
- MSP signaling is mediated through a receptor tyrosine kinase and PI-3 kinase pathway.
- MSP specifically targets mature macrophages and keratinocytes, suggesting a role in tissue-specific functions.
- The findings suggest that MSP plays a role in tissue injury and wound healing processes through the stimulation of macrophages and keratinocytes.