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Papers In Press, published online ahead of print April 1, 2004
Faculté de Médecine, INSERM U145, Nice 06107
Corresponding Author: peraldis{at}unice.fr
One of the cellular mechanisms used to prevent continuous and enhanced activation in response to growth factors is the internalization and the 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 ubiquitinates directly VEGF-R2, we expressed an ubiquitin ligase-deficient mutant Nedd4C854S. In 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 conclusion, 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.
J. Biol. Chem, 10.1074/jbc.M311802200
Submitted on October 28, 2003
Revised on March 1, 2004
Accepted on April 1, 2004
Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation
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