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Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization

Monami, Giada
; 
Emiliozzi, Velia
; 
Morrione, Andrea
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Post-print
Date
2008-02-19
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Department
Biology
Subject
Grb10
 IGF-IR
 Nedd4
 Ubiquitin
 Internalization
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http://hdl.handle.net/20.500.12613/7110
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DOI
https://doi.org/10.1002/jcp.21405
Abstract
The adaptor protein Grb10 is an interacting partner of the IGF-I receptor (IGF-IR) and the insulin receptor (IR). Previous work from our laboratory has established the role of Grb10 as a negative regulator of IGF-IR-dependent cell proliferation. We have shown that Grb10 binds the E3 ubiquitin ligase Nedd4 and promotes IGF-I-stimulated ubiquitination, internalization, and degradation of the IGF-IR, thereby giving rise to long-term attenuation of signaling. Recent biochemical evidence suggests that tyrosine-kinase receptors (RTK) may not be polyubiquitinated but monoubiquitinated at multiple sites (multiubiquitinated). However, the type of ubiquitination of the IGF-IR is still not defined. Here we show that the Grb10/Nedd4 complex upon ligand stimulation mediates multiubiquitination of the IGF-IR, which is required for receptor internalization. Moreover, Nedd4 by promoting IGF-IR ubiquitination and internalization contributes with Grb10 to negatively regulate IGF-IR-dependent cell proliferation. We also demonstrate that the IGF-IR is internalized through clathrin-dependent and-independent pathways. Grb10 and Nedd4 remain associated with the IGF-IR in early endosomes and caveosomes, where they may participate in sorting internalized receptors. Grb10 and Nedd4, unlike the IGF-IR, which is targeted for lysosomal degradation are not degraded and likely directed into recycling endosomes. These results indicate that Grb10 and Nedd4 play a critical role in mediating IGF-IR down-regulation by promoting ligand-dependent multiubiquitination of the IGF-IR, which is required for receptor internalization and regulates mitogenesis.
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Monami, G., Emiliozzi, V. and Morrione, A. (2008), Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. J. Cell. Physiol., 216: 426-437. https://doi.org/10.1002/jcp.21405
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Wiley
This is the peer reviewed version of the following article: Monami, G., Emiliozzi, V. and Morrione, A. (2008), Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. J. Cell. Physiol., 216: 426-437. https://doi.org/10.1002/jcp.21405
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Journal of Cellular Physiology, Vol. 216, Iss. 2
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