c-Jun N-terminal kinase activation is required for the inhibition of neovascularization by thrombospondin-1.
Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis that acts directly on endothelial cells via the CD36 surface receptor molecule to halt their migration, proliferation, and morphogenesis in vitro and to block neovascularization in vivo. Here we show that inhibitory signals elicited by TSP-1 did not alter the ability of inducers of angiogenesis to activate p42 and p44 mitogen-activated protein kinase (MAPK). Rather, TSP-1 induced a rapid and transient activation of c-Jun N-terminal kinases (JNK). JNK activation by TSP-1 required engagement of CD36, as it was blocked by antagonistic CD36 antibodies and stimulated by short anti-angiogenic peptides derived from TSP-1 that act exclusively via CD36. TSP-1 inhibition of corneal neovascularization induced by bFGF was severely impaired in mice null for JNK-1, pointing to a critical role for this stress-activated kinase in the inhibition of neovascularization by TSP-1.
Jiménez
B
B
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Volpert
O V
OV
Reiher
F
F
Chang
L
L
Muñoz
A
A
Karin
M
M
Bouck
N
N
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D018955:CD36 Antigens / Q000502:physiology; D002196:Capillaries / Q000166:cytology; D002478:Cells, Cultured / Q000187:drug effects; D003315:Cornea / Q000098:blood supply; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008222:Lymphokines / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D018955:CD36 Antigens; D015853:Cysteine Proteinase Inhibitors; D016228:Endothelial Growth Factors; D005419:Flavonoids; D008222:Lymphokines; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one