SH3KBP1-binding protein 1 prevents epidermal growth factor receptor degradation by the interruption of c-Cbl-CIN85 complex

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.