Inhibition of endothelial cell proliferation by the recombinant kringle domain of tissue-type plasminogen activator

Biochem Biophys Res Commun. 2003 May 16;304(4):740-6. doi: 10.1016/s0006-291x(03)00656-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Angiogenesis Inhibitors / metabolism
  • Angiostatins
  • Animals
  • Cattle
  • Cell Division / physiology*
  • Cells, Cultured
  • Chick Embryo
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Fibroblast Growth Factor 2 / metabolism
  • Humans
  • Kringles* / genetics
  • Molecular Sequence Data
  • Neovascularization, Physiologic
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Pichia / genetics
  • Pichia / metabolism
  • Plasminogen / genetics
  • Plasminogen / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism*
  • Sequence Alignment
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism*


  • Angiogenesis Inhibitors
  • Peptide Fragments
  • Recombinant Proteins
  • Fibroblast Growth Factor 2
  • Angiostatins
  • Plasminogen
  • Tissue Plasminogen Activator