2000 Fiscal Year Final Research Report Summary
Regulation of endothelial cell behavior by dystroglycan in neovascularization
| Project/Area Number |
11470028
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
KANOH Yumiko Department of Structural Analysis, Senior Staff, 循環器形態部, 室長 (30214498)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Laminin / Fibronectin / Endothelial cell / Dystroglycan / Integrin / Neovascularization / Cytoskeleton |
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| Research Abstract |
We investigated a role of dystroglycan in the control of endothelial cell behavior in angiogenetic processes. The binding between endothelial cells and laminin-10 and -11 was dependent on endothelial dystroglycan, and was inhibited by heparin sulfate. It is well known that endothelial cells undergo migration, proliferation and tube formation in angeogenesis. All of these processes was regulated by dystroglycan. Expression of dystroglycan by endothelilal cell was cell cycle-dependent. The expression level was very low in G0 phase, in contrast to the high level expression in G2/M and S phases. Thus, endothelial expression of dystroglycan is under dynamic regulation and the expressed dystroglycan is involved in the control of cell behaviors.
Histochemical analysis showed that expression of dystroglycan was barely detectable both in the arteries and veins in the normal tissues whereas it was expressed at a high level in newly synthesized blood vessels in cancer tissues. To explore dystroglycan-dependent intracellular signal transduction cascade, we searched for a binding protein which associated with the intracellular domain of dystroglycan, and identified MAGI-1 as a candidate interactor of dystroglycan. MAGI-1 has two WW-domains and five PDZ domains. MAGI-1 bound to dystrolgycan by its WW-domains. MAGI-1 also bound to beta catenin by its fifth PDZ domain. Binding between MAGI-1 and beta catenin inhibited beta catenin degradation, and activated beta catenin - TCF/LEF1 cascade. These results indicated the presence of a signaling cascade between dystroglycan and the beta ctenin/TCF/LEF1 system linked by MAGI-1.
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