Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Calcium-Binding Proteins / chemistry
-
Calcium-Binding Proteins / metabolism*
-
Cardiovascular Agents / metabolism*
-
Cell Line
-
Endothelial Cells / drug effects
-
Endothelial Cells / metabolism
-
Fibroblast Growth Factor 1 / genetics
-
Fibroblast Growth Factor 1 / metabolism*
-
Humans
-
Intercellular Signaling Peptides and Proteins / chemistry
-
Intercellular Signaling Peptides and Proteins / metabolism*
-
Jagged-1 Protein
-
Membrane Proteins / chemistry
-
Membrane Proteins / metabolism*
-
Mice
-
Molecular Weight
-
Multipotent Stem Cells / cytology
-
Multipotent Stem Cells / drug effects
-
Multipotent Stem Cells / metabolism
-
Neural Crest / cytology
-
Peptide Fragments / metabolism*
-
Protein Structure, Tertiary
-
Protein Transport / drug effects
-
Receptor, PAR-1 / metabolism
-
Receptors, Fibroblast Growth Factor / metabolism
-
Receptors, Notch / metabolism
-
Receptors, Thrombin
-
Serrate-Jagged Proteins
-
Signal Transduction / drug effects
-
Thrombin / pharmacology*
-
Transcription, Genetic / drug effects
Substances
-
Calcium-Binding Proteins
-
Cardiovascular Agents
-
Intercellular Signaling Peptides and Proteins
-
JAG1 protein, human
-
Jag1 protein, mouse
-
Jagged-1 Protein
-
Membrane Proteins
-
Peptide Fragments
-
Receptor, PAR-1
-
Receptors, Fibroblast Growth Factor
-
Receptors, Notch
-
Receptors, Thrombin
-
Serrate-Jagged Proteins
-
Fibroblast Growth Factor 1
-
Thrombin