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dc.creatorMonami, Giada
dc.creatorEmiliozzi, Velia
dc.creatorMorrione, Andrea
dc.date.accessioned2021-11-09T15:40:41Z
dc.date.available2021-11-09T15:40:41Z
dc.date.issued2008-02-19
dc.identifier.citationMonami, 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.issn0021-9541
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/7090
dc.identifier.urihttp://hdl.handle.net/20.500.12613/7110
dc.description.abstractThe 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.extent39 pages
dc.languageEnglish
dc.language.isoeng
dc.relation.ispartofFaculty/ Researcher Works
dc.relation.haspartJournal of Cellular Physiology, Vol. 216, Iss. 2
dc.relation.isreferencedbyWiley
dc.relation.isreferencedbyThis 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.rightsAll Rights Reserved
dc.subjectGrb10
dc.subjectIGF-IR
dc.subjectNedd4
dc.subjectUbiquitin
dc.subjectInternalization
dc.titleGrb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization
dc.typeText
dc.type.genrePost-print
dc.description.departmentBiology
dc.relation.doihttps://doi.org/10.1002/jcp.21405
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.schoolcollegeTemple University. College of Science and Technology
dc.creator.orcidMorrione|0000-0002-2319-7884
dc.temple.creatorMorrione, Andrea
refterms.dateFOA2021-11-09T15:40:41Z


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