Alpha 5 beta 1 integrin activates an NF-kappa B-dependent program of gene expression important for angiogenesis and inflammation.
GeneCalling, a genome-wide method of mRNA profiling, reveals that endothelial cells adhering to fibronectin through the alpha 5 beta 1 integrin, but not to laminin through the alpha 2 beta 1 integrin, undergo a complex program of gene expression. Several of the genes identified are regulated by the NF-kappa B transcription factor, and many are implicated in the regulation of inflammation and angiogenesis. Adhesion of endothelial cells to fibronectin activates NF-kappa B through a signaling pathway requiring Ras, phosphatidylinositol 3-kinase, and Rho family proteins, whereas adhesion to laminin has a limited effect. Retroviral transfer of the superrepressor of NF-kappa B, I kappa B-2A, blocks basic fibroblast growth factor-induced angiogenesis in vivo. These results suggest that engagement of the alpha 5 beta 1 integrin promotes an NF-kappa B-dependent program of gene expression that coordinately regulates angiogenesis and inflammation.
Cellular Biochemistry and Biophysics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Sharon
S
Klein
Antonin R
AR
de Fougerolles
Pamela
P
Blaikie
Leila
L
Khan
Angela
A
Pepe
Cynthia D
CD
Green
Victor
V
Koteliansky
Filippo G
FG
Giancotti
D000818:Animals; D001672:Biocompatible Materials; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D003094:Collagen; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000503:physiopathology*; D007797:Laminin; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011509:Proteoglycans; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D001672:Biocompatible Materials; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D005353:Fibronectins; D020672:I-kappa B Proteins; D007797:Laminin; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011509:Proteoglycans; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D017469:Receptors, Fibronectin; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D000072000:NF-KappaB Inhibitor alpha; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins