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J. Biol. Chem., Vol. 279, Issue 25, 26754-26761, June 18, 2004

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Grb10 Prevents Nedd4-mediated Vascular Endothelial Growth Factor Receptor-2 Degradation^*

Joseph Murdaca, Caroline Treins, Marie-Noëlle Monthouël-Kartmann, Rodolphe Pontier-Bres, Sharad Kumar¶, Emmanuel Van Obberghen, and Sophie Giorgetti-Peraldi||

From the INSERM U145, Institut Federatif de Recherche 50, Faculté de Médecine, 06107 Nice Cedex 2, France and ^¶Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Adelaide SA 5000, Australia

One of the cellular mechanisms used to prevent continuous and enhanced activation in response to growth factors is the internalization and degradation of their receptors. Little is known about the molecular mechanisms involved in vascular endothelial growth factor receptor-2 (VEGF-R2) degradation. In a previous work, we have shown that the adaptor protein Grb10 is a positive regulator of the VEGF signaling pathway. Indeed, VEGF stimulates Grb10 expression, and Grb10 overexpression induces an increase in the amount and the tyrosine phosphorylation of VEGF-R2. In the present manuscript, we demonstrate that Grb10 stimulates VEGF-R2 expression by inhibiting the Nedd4-mediated VEGF-R2 degradation. First, we show that proteasome inhibition by MG132 induces an increase in VEGF-R2 amount, and that VEGF-R2 is ubiquitinated in response to VEGF. Expression of Nedd4, a HECT domain-containing ubiquitin ligase, induces the disappearance of VEGF-R2 in cells, suggesting that Nedd4 is involved in VEGF-R2 degradation. To determine whether Nedd4 directly ubiquitinates VEGF-R2, we expressed a ubiquitin ligase-deficient mutant Nedd4C854S. In the presence of Nedd4C854S, VEGF-R2 is expressed and ubiquitinated. These results suggest that VEGF-R2 is ubiquitinated but that Nedd4 is not involved in this process. Finally, we show that Grb10 constitutively associates with Nedd4. Co-expression of Nedd4 and Grb10 restores the expression of VEGF-R2, suggesting that Grb10 inhibits the Nedd4-mediated degradation of VEGF-R2. In this study, we show that Grb10 acts as a positive regulator in VEGF-R2 signaling and protects VEGF-R2 from degradation by interacting with Nedd4, a component of the endocytic machinery.

Received for publication, October 28, 2003 , and in revised form, March 1, 2004.

^* This research was supported by funds from INSERM, Association pour la Recherche contre le Cancer (ARC Grants 5492 and 3293), and University of Nice Sophia-Antipolis, Région Provence-Alpes Coted'Azur, France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche (France).

^|| To whom correspondence should be addressed. Tel.: 334-9337-7797; Fax: 334-9381-5432; E-mail: peraldis{at}unice.fr.

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