PubMed:18286479 JSONTXT

{"project":"bionlp-st-epi-2011-training","denotations":[{"id":"T1","span":{"begin":0,"end":5},"obj":"Protein"},{"id":"T2","span":{"begin":6,"end":11},"obj":"Protein"},{"id":"T3","span":{"begin":48,"end":83},"obj":"Protein"},{"id":"T4","span":{"begin":140,"end":145},"obj":"Protein"},{"id":"T5","span":{"begin":179,"end":193},"obj":"Protein"},{"id":"T6","span":{"begin":195,"end":201},"obj":"Protein"},{"id":"T7","span":{"begin":211,"end":227},"obj":"Protein"},{"id":"T8","span":{"begin":229,"end":231},"obj":"Protein"},{"id":"T9","span":{"begin":296,"end":301},"obj":"Protein"},{"id":"T10","span":{"begin":329,"end":335},"obj":"Protein"},{"id":"T11","span":{"begin":385,"end":390},"obj":"Protein"},{"id":"T12","span":{"begin":404,"end":413},"obj":"Protein"},{"id":"T13","span":{"begin":421,"end":426},"obj":"Protein"},{"id":"T14","span":{"begin":440,"end":445},"obj":"Protein"},{"id":"T15","span":{"begin":513,"end":519},"obj":"Protein"},{"id":"T16","span":{"begin":788,"end":794},"obj":"Protein"},{"id":"T17","span":{"begin":839,"end":844},"obj":"Protein"},{"id":"T18","span":{"begin":845,"end":850},"obj":"Protein"},{"id":"T19","span":{"begin":919,"end":925},"obj":"Protein"},{"id":"T20","span":{"begin":985,"end":990},"obj":"Protein"},{"id":"T21","span":{"begin":1004,"end":1010},"obj":"Protein"},{"id":"T22","span":{"begin":1063,"end":1068},"obj":"Protein"},{"id":"T23","span":{"begin":1092,"end":1098},"obj":"Protein"},{"id":"T24","span":{"begin":1158,"end":1164},"obj":"Protein"},{"id":"T25","span":{"begin":1234,"end":1239},"obj":"Protein"},{"id":"T26","span":{"begin":1244,"end":1249},"obj":"Protein"},{"id":"T27","span":{"begin":1277,"end":1283},"obj":"Protein"},{"id":"T28","span":{"begin":1381,"end":1386},"obj":"Protein"},{"id":"T29","span":{"begin":1391,"end":1396},"obj":"Protein"},{"id":"T30","span":{"begin":1409,"end":1415},"obj":"Protein"},{"id":"T31","span":{"begin":1552,"end":1557},"obj":"Protein"},{"id":"T32","span":{"begin":1562,"end":1567},"obj":"Protein"},{"id":"T33","span":{"begin":1602,"end":1608},"obj":"Protein"},{"id":"T34","span":{"begin":1682,"end":1688},"obj":"Protein"}],"text":"Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization.\nThe 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."}