Endostatin regulates endothelial cell adhesion and cytoskeletal organization.
Endostatin, an endogenous angiogenesis inhibitor, attenuates endothelial cell migration through an unknown mechanism. We show that endostatin induced tyrosine phosphorylation of focal adhesion kinase and paxillin, and promoted formation of focal adhesions and actin stress fibers, similar to fibroblast growth factor-2 (FGF-2). In cells cotreated with endostatin and FGF-2, focal adhesions and actin stress fibers were decreased, indicating that endostatin disturbs cell-matrix adhesion. Reduced tyrosine phosphorylation and cytoplasmic relocalization of beta-catenin in cells treated with FGF-2 and endostatin indicates that loosening of cell-cell adhesion is also disturbed by endostatin. These data provide a molecular basis both for the lack of effect of endostatin on the normal, quiescent vasculature, and its antagonistic effects on stimulated tumor vessels.
Dixelius
Johan
J
Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden.
Cross
Michael
M
Matsumoto
Taro
T
Sasaki
Takako
T
Timpl
Rupert
R
Claesson-Welsh
Lena
L
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000494:pharmacology* / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000502:physiology; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051419:Paxillin; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D051176:beta Catenin
D000199:Actins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D043169:Endostatins; D051419:Paxillin; D010446:Peptide Fragments; D010750:Phosphoproteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D051176:beta Catenin; D016222:Fibroblast Growth Factor 2; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases