Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin.
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.
Bix
Gregory
G
Department of Pathology, Anatomy and Cell Biology, Rm. 249 JAH, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107, USA.
Fu
Jian
J
Gonzalez
Eva M
EM
Macro
Laura
L
Barker
Amy
A
Campbell
Shelly
S
Zutter
Mary M
MM
Santoro
Samuel A
SA
Kim
Jiyeun K
JK
Höök
Magnus
M
Reed
Charles C
CC
Iozzo
Renato V
RV
D000199:Actins / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004338:Drug Combinations; D004721:Endoplasmic Reticulum / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism / Q000502:physiology*; D006497:Heparan Sulfate / Q000737:chemistry; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin / Q000737:chemistry; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D000199:Actins; D003094:Collagen; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004338:Drug Combinations; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D038982:Integrin alpha2beta1; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D020928:Mitogen-Activated Protein Kinases; D010446:Peptide Fragments; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011509:Proteoglycans; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; D000099190:MAP-Kinase-Activated Kinase 2; C059485:matrigel; C071927:perlecan; C496050:PTK2 protein, human