Inhibition of endothelial cell proliferation by the recombinant kringle domain of tissue-type plasminogen activator.
Tissue-type plasminogen activator (tPA) is a multidomain serine protease that converts the zymogen plasminogen to plasmin. tPA contains two kringle domains which display considerable sequence identity with those of angiostatin, an angiogenesis inhibitor. TK1-2, a recombinant kringle domain composed of t-PA kringles 1 and 2 (Ala(90)-Thr(263)), was produced by both bacterial and yeast expression systems. In vitro, TK1-2 inhibited endothelial cell proliferation stimulated by basic fibroblast growth factor, vascular endothelial growth factor, and epidermal growth factor. It did not inhibit proliferation of non-endothelial cells. TK1-2 also inhibited in vivo angiogenesis in the chick embryo chorioallantoic membrane model. These results suggest that the recombinant kringle domain of t-PA is a selective inhibitor of endothelial cell growth and identifies this molecule as a novel anti-angiogenic agent.
Kim
Hyun-Kyung
HK
Cancer Research Institute, Catholic Research Institutes of Medical Sciences, The Catholic University of Korea, 137-701, Seoul, Republic of Korea
Lee
Soo Young
SY
Oh
Ho-Kyun
HK
Kang
Byoung-Hak
BH
Ku
Hyeun-Ju
HJ
Lee
Yoon
Y
Shin
Joo-Young
JY
Hong
Yong-Kil
YK
Joe
Young Ae
YA
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000378:metabolism; D043168:Angiostatins; D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D018082:Kringles / Q000235:genetics; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D043168:Angiostatins; D010958:Plasminogen; D010959:Tissue Plasminogen Activator