Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization
dc.creator | Monami, Giada | |
dc.creator | Emiliozzi, Velia | |
dc.creator | Morrione, Andrea | |
dc.date.accessioned | 2021-11-09T15:40:41Z | |
dc.date.available | 2021-11-09T15:40:41Z | |
dc.date.issued | 2008-02-19 | |
dc.identifier.citation | 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 | |
dc.identifier.issn | 0021-9541 | |
dc.identifier.doi | http://dx.doi.org/10.34944/dspace/7090 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12613/7110 | |
dc.description.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. | |
dc.format.extent | 39 pages | |
dc.language | English | |
dc.language.iso | eng | |
dc.relation.ispartof | Faculty/ Researcher Works | |
dc.relation.haspart | Journal of Cellular Physiology, Vol. 216, Iss. 2 | |
dc.relation.isreferencedby | Wiley | |
dc.relation.isreferencedby | 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 | |
dc.rights | All Rights Reserved | |
dc.subject | Grb10 | |
dc.subject | IGF-IR | |
dc.subject | Nedd4 | |
dc.subject | Ubiquitin | |
dc.subject | Internalization | |
dc.title | Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization | |
dc.type | Text | |
dc.type.genre | Post-print | |
dc.description.department | Biology | |
dc.relation.doi | https://doi.org/10.1002/jcp.21405 | |
dc.ada.note | For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu | |
dc.description.schoolcollege | Temple University. College of Science and Technology | |
dc.creator.orcid | Morrione|0000-0002-2319-7884 | |
dc.temple.creator | Morrione, Andrea | |
refterms.dateFOA | 2021-11-09T15:40:41Z |