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Thrombomodulin functions as a plasminogen receptor to modulate angiogenesis
Author(s) -
Chen PoKu,
Chang BiIng,
Kuo ChengHsiang,
Chen PinShern,
Cho ChiaFong,
Chang ChuanFa,
Shi GueyYueh,
Wu HuaLin
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-227561
Subject(s) - thrombomodulin , angiogenesis , receptor , chemistry , cancer research , microbiology and biotechnology , medicine , biology , thrombin , biochemistry , platelet
Urokinase‐type plasminogen activator (uPA) activates plasminogen (Plg) through a major pericellular proteolytic system involved in cell migration and angiogenesis; however, the Plg receptor that participates in uPA‐mediated Plg activation has not yet been identified. In this study, we demonstrated that thrombomodulin (TM), a type I transmembrane glycoprotein, is a novel Plg receptor that plays a role in pericellular proteolysis and cell migration. Plg activation at the cell surface and the extent of its cell migration‐ and invasion‐promoting effect are cellular TM expression dependent. Direct binding of Plg and the recombinant TM extracellular domain, with a K D of 0.1—0.3 μM, was determined through surface plasmon resonance analysis. Colocalization of TM, Plg, and the uPA receptor within plasma membrane lipid rafts, at the leading edge of migrating endothelial cells, was demonstrated and was also shown to overlap with areas of major pericellular proteolysis. Moreover, the roles of TM and Plg in neoangiogenesis were demonstrated in vivo through the skin wound‐healing model. In conclusion, we propose that TM is a novel Plg receptor that regulates uPA/uPA receptor‐mediated Plg activation and pericellular proteolysis within lipid rafts at the leading edge of migrating cells during angiogenesis.—Chen, P.‐K., Chang, B.‐I., Kuo, C.‐H., Chen, P.‐S., Cho, C.‐F., Chang, C.‐F., Shi, G.‐Y., Wu, H.‐L. Thrombomodulin functions as a plasminogen receptor to modulate angiogenesis. FASEB J . 27, 4520–4531 (2013). www.fasebj.org