Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin.

The Journal of Cell Biology
Gregory J BixR V Iozzo

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, alpha2beta1 integrin, and provide an initial investigation of the intracellular signaling events that lead to endorepellin antiangiogenic activity. The interaction between endorepellin and alpha2beta1 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.

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Citations

May 26, 2009·Molecules and Cells·Renato V IozzoAlexander Nyström
Sep 3, 2010·Journal of Mammary Gland Biology and Neoplasia·Ori MallerPepper Schedin
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Methods Mentioned

BETA
X-ray
surface plasmon resonance
ELISA
GTPases
Transfection
protein kinase assay

Software Mentioned

Adobe Photoshop
BIAevaluation
SPR

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