Novel cross-talk between three cardiovascular regulators: thrombin cleavage fragment of Jagged1 induces fibroblast growth factor 1 expression and release.
Angiogenesis is controlled by several regulatory mechanisms, including the Notch and fibroblast growth factor (FGF) signaling pathways. FGF1, a prototype member of FGF family, lacks a signal peptide and is released through an endoplasmic reticulum-Golgi-independent mechanism. A soluble extracellular domain of the Notch ligand Jagged1 (sJ1) inhibits Notch signaling and induces FGF1 release. Thrombin, a key protease of the blood coagulation cascade and a potent inducer of angiogenesis, stimulates rapid FGF1 release through a mechanism dependent on the major thrombin receptor protease-activated receptor (PAR) 1. This study demonstrates that thrombin cleaves Jagged1 in its extracellular domain. The sJ1 form produced as a result of thrombin cleavage inhibits Notch-mediated CBF1/Suppressor of Hairless [(Su(H)]/Lag-1-dependent transcription and induces FGF1 expression and release. The overexpression of Jagged1 in PAR1 null cells results in a rapid thrombin-induced export of FGF1. These data demonstrate the existence of novel cross-talk between thrombin, FGF, and Notch signaling pathways, which play important roles in vascular formation and remodeling.
Duarte
Maria
M
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Kolev
Vihren
V
Kacer
Doreen
D
Mouta-Bellum
Carla
C
Soldi
Raffaella
R
Graziani
Irene
I
Kirov
Aleksandr
A
Friesel
Robert
R
Liaw
Lucy
L
Small
Deena
D
Verdi
Joseph
J
Maciag
Thomas
T
Prudovsky
Igor
I
D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D002317:Cardiovascular Agents / Q000378:metabolism*; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology; D010446:Peptide Fragments / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D018179:Receptors, Thrombin; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D002135:Calcium-Binding Proteins; D002317:Cardiovascular Agents; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D017468:Receptors, Fibroblast Growth Factor; D051880:Receptors, Notch; D018179:Receptors, Thrombin; D000072099:Serrate-Jagged Proteins; D016220:Fibroblast Growth Factor 1; D013917:Thrombin
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