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Grb10/Nedd4‐mediated multiubiquitination of the insulin‐like growth factor receptor regulates receptor internalization
Author(s) -
Monami Giada,
Emiliozzi Velia,
Morrione Andrea
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21405
Subject(s) - internalization , nedd4 , insulin like growth factor 1 receptor , grb10 , insulin receptor , receptor , insulin receptor substrate , microbiology and biotechnology , insulin , insulin like growth factor , biology , endocrinology , growth factor , insulin resistance , genetics , gene , ubiquitin , ubiquitin ligase
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. J. Cell. Physiol. 216: 426–437, 2008. © 2008 Wiley‐Liss, Inc.