DGDA, a local sequence of the kringle 2 domain, is a functional motif of the tissue-type plasminogen activator's antiangiogenic kringle domain.
Antiangiogenic activity can be elicited by the kringle domains 1 and 2 of tissue-type plasminogen activator (TK1-2), or the kringle 2 domain alone. In a previous report, we showed that the anti-migratory effect of TK1-2 is mediated in part by its interference with integrin alpha2beta1. Since integrin alpha2beta1 interacts with collagen type I through the DGEA (Asp-Gly-Glu-Ala) amino acid sequence, and a similar sequence, DGDA (Asp-Gly-Asp-Ala), exists in the kringle 2 domain, we investigated whether the DGDA sequence has a role in antiangiogenic activity of TK1-2. In an adhesion assay, the DGDA peptide inhibited adhesion of human umbilical vein endothelial cells (HUVECs) to immobilized TK1-2. Pretreatment of the DGDA peptide also blocked anti-migratory activity of TK1-2. When the DGDA peptide alone was tested for antiangiogenic activity, it effectively inhibited VEGF-induced migration of HUVECs and tube formation on Matrigel. In addition, the DGDA peptide decreased differentiation of endothelial progenitor cells on collagen type I matrix. These data suggest that the DGDA sequence presents a functional epitope of TK1-2 and that it can be used as a potential novel antiangiogenic peptide.
Kim
Hyun-Kyung
HK
Cancer Research Institute and Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
Joe
Young Ae
YA
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000737:chemistry; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D018082:Kringles; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000737:chemistry / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D009842:Oligopeptides; C547682:aspartyl-glycyl-aspartyl-alanine; D003094:Collagen; D010959:Tissue Plasminogen Activator