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Vol. 19, Issue 11, 4863-4874, November 2008

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

Maria Duarte^*,, Vihren Kolev^*,, 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

Submitted December 12, 2007; Revised July 23, 2008; Accepted August 29, 2008
Monitoring Editor: J. Silvio Gutkind

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.

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

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 used: 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.