Abstract
Ubiquitination of receptor protein-tyrosine kinases (RPTKs) terminates signaling by marking active receptors for degradation. c-Cbl, an adapter protein for RPTKs, positively regulates RPTK ubiquitination in a manner dependent on its variant SRC homology 2 (SH2) and RING finger domains. Ubiquitin-protein ligases (or E3s) are the components of ubiquitination pathways that recognize target substrates and promote their ligation to ubiquitin. The c-Cbl protein acted as an E3 that can recognize tyrosine-phosphorylated substrates, such as the activated platelet-derived growth factor receptor, through its SH2 domain and that recruits and allosterically activates an E2 ubiquitin-conjugating enzyme through its RING domain. These results reveal an SH2-containing protein that functions as a ubiquitin-protein ligase and thus provide a distinct mechanism for substrate targeting in the ubiquitin system.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Cell Line
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Humans
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Ligases / chemistry
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Ligases / metabolism*
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Molecular Sequence Data
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Phosphotyrosine / metabolism
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Point Mutation
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-cbl
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Recombinant Fusion Proteins / metabolism
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Sequence Alignment
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Signal Transduction
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Ubiquitin-Conjugating Enzymes*
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Ubiquitin-Protein Ligases
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Ubiquitins / metabolism*
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src Homology Domains
Substances
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Ubiquitins
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Phosphotyrosine
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Ubiquitin-Conjugating Enzymes
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ubiquitin-conjugating enzyme UBC4
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Receptor Protein-Tyrosine Kinases
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Receptor, Platelet-Derived Growth Factor beta
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Ligases
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CBL protein, human