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Angiomotin: an angiostatin binding protein that regulates endothelial cell migration and tube formation
B Troyanovsky1, T Levchenko, G Månsson
1Center for Genomics Research and Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Abstract:
Angiostatin, a circulating inhibitor of angiogenesis, was identified by its ability to maintain dormancy of established metastases in vivo. In vitro, angiostatin inhibits endothelial cell migration, proliferation, and tube formation, and induces apoptosis in a cell type-specific manner. We have used a construct encoding the kringle domains 1--4 of angiostatin to screen a placenta yeast two-hybrid cDNA library for angiostatin-binding peptides. Here we report the identification of angiomotin, a novel protein that mediates angiostatin inhibition of migration and tube formation of endothelial cells. In vivo, angiomotin is expressed in the endothelial cells of capillaries as well as larger vessels of the human placenta. Upon expression of angiomotin in HeLa cells, angiomotin bound and internalized fluorescein-labeled angiostatin. Transfected angiomotin as well as endogenous angiomotin protein were localized to the leading edge of migrating endothelial cells. Expression of angiomotin in endothelial cells resulted in increased cell migration, suggesting a stimulatory role of angiomotin in cell motility. However, treatment with angiostatin inhibited migration and tube formation in angiomotin-expressing cells but not in control cells. These findings indicate that angiostatin inhibits cell migration by interfering with angiomotin activity in endothelial cells.
Insights
Researchers identified angiomotin, a protein that mediates angiostatin
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Angiostatin is a known inhibitor of angiogenesis, crucial for tumor growth and metastasis.
- Its mechanism of action involves inhibiting endothelial cell functions like migration and proliferation.
- Understanding the specific molecular targets of angiostatin is key to developing anti-angiogenic therapies.
Purpose of the Study:
- To identify novel proteins that bind angiostatin and mediate its anti-angiogenic effects.
- To characterize the function of angiomotin in endothelial cell behavior and its interaction with angiostatin.
Main Methods:
- Yeast two-hybrid screening of a placenta cDNA library using angiostatin kringle domains.
- Expression and localization studies of angiomotin in HeLa and endothelial cells.
- Functional assays measuring endothelial cell migration and tube formation in response to angiostatin and angiomotin.
Main Results:
- Angiomotin was identified as a novel angiostatin-binding protein.
- Angiomotin mediates angiostatin's inhibition of endothelial cell migration and tube formation.
- Angiomotin is expressed in placental endothelial cells and localizes to the leading edge of migrating cells.
- While angiomotin promotes cell migration, angiostatin inhibits this process in angiomotin-expressing cells.
Conclusions:
- Angiomotin is a key mediator of angiostatin's anti-angiogenic activity.
- Angiostatin exerts its inhibitory effects by interfering with angiomotin function in endothelial cells.
- This discovery provides a new molecular target for anti-angiogenesis strategies.