Soluble M6P/IGF2R released by TACE controls angiogenesis via blocking plasminogen activation.
Circ Res
; 108(6): 676-85, 2011 Mar 18.
Article
en En
| MEDLINE
| ID: mdl-21273553
ABSTRACT
RATIONALE The urokinase plasminogen activator (uPA) system is among the most crucial pericellular proteolytic systems associated with the processes of angiogenesis. We previously identified an important regulator of the uPA system in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R). OBJECTIVE:
Here, we wanted to clarify whether and how did the soluble form of M6P/IGF2R (sM6P/IGF2R) contribute to modulation of the uPA system. METHODS ANDRESULTS:
By using specific inhibitors and RNA interference, we show that the tumor necrosis factor α convertase (TACE, ADAM-17) mediates the release of the ectodomain of M6P/IGF2R from human endothelial cells. We demonstrate further that sM6P/IGF2R binds plasminogen (Plg) and thereby prevents Plg from binding to the cell surface and uPA, ultimately inhibiting in this manner Plg activation. Furthermore, peptide 18-36 derived from the Plg-binding site of M6P/IGF2R mimics sM6P/IGF2R in the inhibition of Plg activation and blocks cancer cell invasion in vitro, endothelial cell invasion in vivo, and tumor growth in vivo.CONCLUSIONS:
The interaction of sM6P/IGF2R with Plg may be an important regulatory mechanism to inhibit migration of cells using the uPA/uPAR system.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Plasminógeno
/
Activador de Plasminógeno de Tipo Uroquinasa
/
Movimiento Celular
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Receptor IGF Tipo 2
/
Neovascularización Fisiológica
/
Células Endoteliales
/
Proteínas ADAM
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Circ Res
Año:
2011
Tipo del documento:
Article
País de afiliación:
Austria