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J Cell Physiol ; 214(3): 828-37, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17879962

RESUMEN

Thrombospondin-1 (TSP-1) is an extracellular matrix protein that modulates focal adhesion in mammalian cells and exhibits dual roles in angiogenesis. In a previous work, we showed that a recombinant 18 kDa protein encompassing the N-terminal residues 1-174 of human TSP-1 (TSP18) induced tubulogenesis of human umbilical vein endothelial cells and protected them from apoptosis. Our results indicated that these effects were possibly mediated by syndecan-4 proteoglycan, since binding of TSP18 to endothelial extracts was inhibited by anti-syndecan-4 antibody. Syndecan-4 is a heparan-sulfate proteoglycan that regulates cell-matrix interactions and is the only member of its family present in focal adhesions. In this report, we demonstrate that a monoclonal antibody against syndecan-4 blocks TSP18-induced tubulogenesis. Furthermore, through 2D adhesion and 3D angiogenic assays, we demonstrate that two sequences, TSP Hep I and II, retain the major pro-angiogenic activity of TSP18. These TSP-1 motifs also compete with the fibronectin Hep II domain for binding to syndecan-4 on endothelial cell surface, indicating that they may exert their effects by interfering with the recognition of fibronectin by syndecan-4. Additionally, TSP18 and its derived peptides activate the PKC-dependent Akt-PKB signaling pathway. Blockage of PKC activation prevented HUVEC spreading when seeded on TSP18 fragment, and on TSP Hep I and TSP Hep II peptides, but not on gelatin-coated substrates. Our results identify syndecan-4 as a novel receptor for the N-terminus of TSP-1 and suggest that TSP-1 N-terminal pro-angiogenic activity is linked to its capacity of interfering with syndecan-4 functions in the course of cell adhesion.


Asunto(s)
Proteínas Angiogénicas/metabolismo , Endotelio/irrigación sanguínea , Neovascularización Fisiológica , Sindecano-4/metabolismo , Trombospondina 1/química , Trombospondina 1/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Anticuerpos/farmacología , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Endotelio/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Fibronectinas/metabolismo , Humanos , Datos de Secuencia Molecular , Neovascularización Fisiológica/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Relación Estructura-Actividad , Porcinos
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