Source:http://linkedlifedata.com/resource/pubmed/id/18632619
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
14
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pubmed:dateCreated |
2008-7-17
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pubmed:abstractText |
The insulin-like growth factor receptor (IGF-IR) plays several pivotal roles in cancer. Although most studies on the function of the IGF-IR have been attributed to kinase-dependent signaling, recent findings by our group and others have implicated biological roles mediated by ubiquitination of the receptor. As previously reported, the E3 ligases Mdm2 and Nedd4 mediate IGF-IR ubiquitination. Here we show that c-Cbl is a novel E3 ligase for IGF-IR. On ligand stimulation, both Mdm2 and c-Cbl associate with IGF-IR and mediate receptor polyubiquitination. Whereas Mdm2 catalyzed lysine 63 (K63) chain ubiquitination, c-Cbl modified IGF-IR through K48 chains. Mdm2-mediated ubiquitination occurred when cells were stimulated with a low concentration (5 ng/mL) of IGF-I, whereas c-Cbl required high concentrations (50-100 ng/mL). Mdm2-ubiquitinated IGF-IR was internalized through the clathrin endocytic pathway whereas c-Cbl-ubiquitinated receptors were endocytosed via the caveolin route. Taken together, our results show that c-Cbl constitutes a new ligase responsible for the ubiquitination of IGF-IR and that it complements the action of Mdm2 on ubiquitin lysine residue specificity, responsiveness to IGF-I, and type of endocytic pathway used. The actions and interactions of Mdm2 and c-Cbl in the ubiquitination and endocytosis of IGF-IR may have implications in cancer. In addition, identification and functional characterization of new E3 ligases are important in itself because therapeutic targeting of substrate-specific E3 ligases is likely to represent a critical strategy in future cancer treatment.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Endosomal Sorting Complexes...,
http://linkedlifedata.com/resource/pubmed/chemical/MDM2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Nedd4 ubiquitin protein ligases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-cbl,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-mdm2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, IGF Type 1,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin-Protein Ligases
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1538-7445
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
68
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5669-77
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:18632619-Cell Line, Tumor,
pubmed-meshheading:18632619-Endocytosis,
pubmed-meshheading:18632619-Endosomal Sorting Complexes Required for Transport,
pubmed-meshheading:18632619-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:18632619-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:18632619-Humans,
pubmed-meshheading:18632619-Microscopy, Confocal,
pubmed-meshheading:18632619-Models, Biological,
pubmed-meshheading:18632619-Neoplasms,
pubmed-meshheading:18632619-Proto-Oncogene Proteins c-cbl,
pubmed-meshheading:18632619-Proto-Oncogene Proteins c-mdm2,
pubmed-meshheading:18632619-Receptor, IGF Type 1,
pubmed-meshheading:18632619-Ubiquitin,
pubmed-meshheading:18632619-Ubiquitin-Protein Ligases
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pubmed:year |
2008
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pubmed:articleTitle |
Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis.
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pubmed:affiliation |
Department of Oncology and Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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