Thrombomodulin functions as a plasminogen receptor to modulate angiogenesis.
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 KD 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.
1Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan 701, Taiwan. H.-L.W., halnwu@mail.ncku.edu.tw.
Po-Ku
PK
Chen
Bi-Ing
BI
Chang
Cheng-Hsiang
CH
Kuo
Pin-Shern
PS
Chen
Chia-Fong
CF
Cho
Chuan-Fa
CF
Chang
Guey-Yueh
GY
Shi
Hua-Lin
HL
Wu
D000818:Animals; D016466:CHO Cells; D002465:Cell Movement; D006224:Cricetinae; D003412:Cricetulus; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D000072483:Placenta Growth Factor; D010958:Plasminogen / Q000378:metabolism*; D011257:Pregnancy Proteins / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D012867:Skin / Q000098:blood supply; D018180:Thrombomodulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014945:Wound Healing
C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D018180:Thrombomodulin; D000072483:Placenta Growth Factor; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator
cell migration; endothelial cells; lipid raft; pericellular proteolysis