The kringle domain of tissue-type plasminogen activator inhibits extracellular matrix-induced adhesion and migration of endothelial cells.
The recombinant two-kringle domain of human tissue-type plasminogen activator (TK1-2) was found to inhibit angiogenesis and tumor growth. Recently, we found that TK1-2 inhibits adhesive differentiation of endothelial progenitor cells, and its contribution to tumor angiogenesis. In this study, we investigated the effects of TK1-2 on extracellular matrix-induced adhesion, signaling, and migration in order to understand the mechanism of action of TK1-2. When human umbilical vein endothelial cells were pretreated with TK1-2 and then allowed to adhere to immobilized fibronectin, vitronectin, or gelatin, cell adhesion to all the tested matrices decreased dose-dependently upon TK1-2 treatment. TK1-2 also inhibited the formation of actin stress fibers and focal adhesions upon attachment to each matrix. Moreover, fibronectin- and vitronectin-induced endothelial cell migration was dose-dependently inhibited by TK1-2. TK1-2 also suppressed fibronectin-induced ERK1/2 phosphorylation. Hence the results suggest that disturbance of extracellular matrix-induced adhesion, signaling, and migration of endothelial cells is involved in the anti-angiogenic activity of TK1-2.
Lee
Byung Hun
BH
Cancer Research Institute and Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Kim
Hyun-Kyung
HK
Joe
Young Ae
YA
D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D005780:Gelatin / Q000378:metabolism; D006801:Humans; D018082:Kringles; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D010843:Pichia / Q000235:genetics; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology; D022502:Stress Fibers / Q000378:metabolism; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D019096:Vitronectin / Q000378:metabolism
D016895:Culture Media, Serum-Free; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019096:Vitronectin; D005780:Gelatin; D010959:Tissue Plasminogen Activator