Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through α2β1 integrin

Gregory Bix, Jian Fu, Eva M. Gonzalez, Laura Macro, Amy Barker, Shelly Campbell, Mary M. Zutter, Samuel A. Santoro, Jiyeun K. Kim, Magnus Höök, Charles C. Reed, Renato V. Iozzo

Research output: Contribution to journalArticlepeer-review

238 Scopus citations


Endorepellin, the COOH-terminal domain of the heparan sulfate proteoglycan perlecan, inhibits several aspects of angiogenesis. We provide evidence for a novel biological axis that links a soluble fragment of perlecan protein core to the major cell surface receptor for collagen I, α2β1 integrin, and provide an initial investigation of the intracellular signaling events that lead to endorepellin anti-angiogenic activity. The interaction between endorepellin and α2β1 integrin triggers a unique signaling pathway that causes an increase in the second messenger cAMP; activation of two proximal kinases, protein kinase A and focal adhesion kinase; transient activation of p38 mitogen-activated protein kinase and heat shock protein 27, followed by a rapid down-regulation of the latter two proteins; and ultimately disassembly of actin stress fibers and focal adhesions. The end result is a profound block of endothelial cell migration and angiogenesis. Because perlecan is present in both endothelial and smooth muscle cell basement membranes, proteolytic activity during the initial stages of angiogenesis could liberate antiangiogenic fragments from blood vessels' walls, including endorepellin.

Original languageEnglish (US)
Pages (from-to)97-109
Number of pages13
JournalJournal of Cell Biology
Issue number1
StatePublished - Jul 5 2004


  • Angiogenesis
  • Collagen
  • Endothelial cell
  • LG module
  • Perlecan proteoglycan

ASJC Scopus subject areas

  • Cell Biology


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