Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization.
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.
Mesh Terms:
Animals, Caveolin 1, Cell Line, Cell Proliferation, Clathrin, Endosomal Sorting Complexes Required for Transport, Endosomes, GRB10 Adaptor Protein, Lysosomes, Mice, Multiprotein Complexes, Polyubiquitin, RNA, Small Interfering, Rats, Receptor, IGF Type 1, Receptor, Insulin, Ubiquitin-Protein Ligases, Ubiquitination, Vesicular Transport Proteins
Animals, Caveolin 1, Cell Line, Cell Proliferation, Clathrin, Endosomal Sorting Complexes Required for Transport, Endosomes, GRB10 Adaptor Protein, Lysosomes, Mice, Multiprotein Complexes, Polyubiquitin, RNA, Small Interfering, Rats, Receptor, IGF Type 1, Receptor, Insulin, Ubiquitin-Protein Ligases, Ubiquitination, Vesicular Transport Proteins
J. Cell. Physiol.
Date: Aug. 01, 2008
PubMed ID: 18286479
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