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Published 5 July 2004. doi:10.1083/jcb.200401150
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 1, 97-109
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Article

 Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through {alpha}2ß1 integrin

Gregory Bix1, Jian Fu1, Eva M. Gonzalez1, Laura Macro1, Amy Barker1, Shelly Campbell1, Mary M. Zutter2, Samuel A. Santoro2, Jiyeun K. Kim3, Magnus Höök3, Charles C. Reed1, and Renato V. Iozzo1

1 Department of Pathology, Anatomy and Cell Biology, and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
2 Department of Pathology, Vanderbilt University, Nashville, TN 37232
3 Center for Extracellular Matrix Biology, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030

Address correspondence to Renato V. Iozzo, Dept. of Pathology, Anatomy and Cell Biology, Rm. 249 JAH, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107. Tel.: (215) 503-2208. Fax: (215) 523-7969. email: Iozzo{at}mail.jci.tju.edu


Abstract
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, {alpha}2ß1 integrin, and provide an initial investigation of the intracellular signaling events that lead to endorepellin antiangiogenic activity. The interaction between endorepellin and {alpha}2ß1 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.

Key Words: perlecan proteoglycan; angiogenesis; endothelial cell; collagen; LG module

The online version of this article includes supplemental material.

Abbreviations used in this paper: Ad, adenovirus; AP, human placental alkaline phosphatase; [cAMP]i, intracellular cAMP; ER, endorepellin; Hsp27, heat shock protein 27; HUVEC, human umbilical vein endothelial cell; LG, laminin G–like; MEC, human microvascular dermal endothelial cell; NMuMg, normal murine mammary gland epithelial cells; PKA, protein kinase A; SPR, surface plasmon resonance spectroscopy.


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