Inactivation of Src family kinases inhibits angiogenesis in vivo: implications for a mechanism involving organization of the actin cytoskeleton.
Inhibition of angiogenesis could be a treatment strategy for diseases such as cancer, rheumatoid arthritis, and diabetic retinopathy. PP2 is a pharmacological inhibitor of Src family kinases and was found to inhibit FGF-2 induced angiogenesis in vivo. Experiments in vitro showed that PP2 inhibited invasive growth and sprouting of both endothelial and vascular smooth muscle cells into a fibrin matrix. PP2 inhibited the formation of lamellopodia and expression of kinase inactive c-Src reduced phosphorylation of cortactin and paxillin, suggesting a model in which Src kinases are involved in organization of the actin cytoskeleton. Consequently, endothelial cells expressing kinase inactive c-Src failed to spread and form cord-like structures on a collagen matrix. These data suggest that pharmacological inactivation of Src family kinases inhibits FGF-2 stimulated angiogenesis by interference with organization of the actin cytoskeleton in both endothelial and vascular smooth muscle cells, which affects cell migration.
Department of Genetics and Pathology, Vascular Biology Unit, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.
Witold W
WW
Kilarski
Natalia
N
Jura
Pär
P
Gerwins
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D051356:Cortactin; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000201:enzymology; D011743:Pyrimidines / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics
C412373:AG 1879; D051356:Cortactin; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D051419:Paxillin; D010750:Phosphoproteins; D011743:Pyrimidines; D016222:Fibroblast Growth Factor 2; D004247:DNA; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1