Abstract
The binding of Cbl-interacting protein of 85 kDa (CIN85) to c-Cbl is important to endocytosis and degradation of epidermal growth factor receptor (EGFR). The proline-arginine motif PXXXPR in c-Cbl and SH3 domains of CIN85 are essential to this interaction. Here, we demonstrated that SH3KBP1-binding protein 1 (SHKBP1), which also contains two PXXXPR motifs, constitutively bound to SH3 domains of CIN85. Importantly, the binding of SHKBP1 prevented the interaction of CIN85 with c-Cbl and inhibited the translocation of CIN85 to EGFR-containing vesicles, thus reducing EGFR degradation and enhancing EGF-induced serum response element transcription activity. Therefore, our results indicated that SHKBP1 could promote EGFR signaling pathway by interrupting c-Cbl-CIN85 complex and inhibiting EGFR degradation.
Copyright © 2011 John Wiley & Sons, Ltd.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Carrier Proteins / metabolism
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Epidermal Growth Factor / metabolism
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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ErbB Receptors / pharmacology
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Genes, Reporter
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HEK293 Cells
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HeLa Cells
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Humans
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Plasmids / genetics
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Plasmids / metabolism
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Protein Interaction Mapping
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Protein Structure, Tertiary
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Protein Transport
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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Signal Transduction
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Transcriptional Activation
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Transfection
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Two-Hybrid System Techniques
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Multiprotein Complexes
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SH3KBP1 protein, human
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Epidermal Growth Factor
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Proto-Oncogene Proteins c-cbl
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ErbB Receptors
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CBL protein, human