Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1

Young Mi Kim, Sewook Hwang, Young Myoeng Kim, Bo Jeong Pyun, Tae Yoon Kim, Seung Taek Lee, Yong Song Gho, Young Guen Kwon

Research output: Contribution to journalArticle

352 Citations (Scopus)

Abstract

Endostatin, a fragment of collagen XVIII, is a potent anti-angiogenic protein, but the molecular mechanism of its action is not yet clear. We examined the effects of endostatin on the biological and biochemical activities of vascular endothelial growth factor (VEGF). Endostatin blocked VEGF-induced tyrosine phosphorylation of KDR/Flk-1 and activation of ERK, p38 MAPK, and p125FAK in human umbilical vein endothelial cells. Endostatin also inhibited the binding of VEGF165 to both endothelial cells and purified extracellular domain of KDR/Flk-1. Moreover, the binding of VEGF121 to KDR/ Flk-1 and VEGF121-stimulated ERK activation were blocked by endostatin. The direct interaction between endostatin and KDR/Flk-1 was confirmed by affinity chromatography. However, endostatin did not bind to VEGF. Our findings suggest that a direct interaction of endostatin with KDR/Flk-1 may be involved in the inhibitory function of endostatin toward VEGF actions and responsible for its potent anti-angiogenic and anti-tumor activities in vivo.

Original languageEnglish
Pages (from-to)27872-27879
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number31
DOIs
Publication statusPublished - 2002 Aug 2

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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