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

Bix G, Fu J, Gonzalez EM, Macro L, Barker A, Campbell S, Zutter MM, Santoro SA, Kim JK, Höök M, Reed CC, Iozzo RV
J Cell Biol. 2004 166 (1): 97-109

PMID: 15240572 · PMCID: PMC2172143 · DOI:10.1083/jcb.200401150

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.

MeSH Terms (41)

Actins Adenoviridae Cell Adhesion Cell Line Cells, Cultured Collagen Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoskeleton Dose-Response Relationship, Drug Down-Regulation Drug Combinations Endoplasmic Reticulum Endothelial Cells Endothelium, Vascular Enzyme Activation Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Focal Adhesions Heparan Sulfate Proteoglycans Heparitin Sulfate Humans Integrin alpha2beta1 Intracellular Signaling Peptides and Proteins Laminin Microscopy, Fluorescence Mitogen-Activated Protein Kinases Models, Biological Myocytes, Smooth Muscle Neovascularization, Physiologic p38 Mitogen-Activated Protein Kinases Peptide Fragments Protein-Serine-Threonine Kinases Protein-Tyrosine Kinases Protein Kinases Protein Structure, Tertiary Proteoglycans Recombinant Proteins rhoA GTP-Binding Protein Signal Transduction Time Factors

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