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Mol. Biol. Cell 19 (11): 4863-4874

Copyright © 2008 by The American Society for Cell Biology.

Novel Cross-Talk between Three Cardiovascular Regulators: Thrombin Cleavage Fragment of Jagged1 Induces Fibroblast Growth Factor 1 Expression and Release

Maria Duarte*,{dagger}, Vihren Kolev*,{ddagger}, Doreen Kacer*, Carla Mouta-Bellum*, Raffaella Soldi*,§, Irene Graziani*,||, Aleksandr Kirov*, Robert Friesel*, Lucy Liaw*, Deena Small, Joseph Verdi*, Thomas Maciag*, and Igor Prudovsky*

*Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074; and Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH 03824

Received for publication December 12, 2007. Revision received July 23, 2008. Accepted for publication August 29, 2008.

Monitoring Editor: J. Silvio Gutkind

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.


This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-12-1237) on September 10, 2008.

Present addresses: {dagger} Alentejo Biotechnology Center (CEBAL), Edifício NERBE, 7800-904 Beja, Portugal;

{ddagger} Cutaneous Biology Research Center, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA 02129;

§ Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112;

|| Department of Clinical Care Medicine and Surgery, University of Florence, Florence 50139, Italy.

Address correspondence to: Igor Prudovsky (prudoi{at}mmc.org)

Abbreviations: caN1, constitutively active Notch1 • CL, cell lysate(s) • CSL, CBF1/Suppressor of Hairless [(Su(H)]/Lag-1 • EGF, epidermal growth factor • DSL, Delta/Serrate/Lag-2 • FGF, fibroblast growth factor • FLJ1, full-length Jagged1 • dnFGFR1, dominant-negative form of fibroblast growth factor receptor 1 • GAPDH, glyceraldehyde-3-phosphate dehydrogenase • MEF, mouse embryo fibroblast • NCSC, neural crest stem cell • PAGE, polyacrylamide gel electrophoresis • PAR, protease-activated receptor • PCR, polymerase chain reaction • RT, reverse transcription • sJ1, soluble Jagged1 • TRAP, thrombin receptor-activated peptide.


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