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A more recent version of this article appeared on July 1, 2004
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Submitted on September 20, 2003
Revised on April 1, 2004
Accepted on April 5, 2004
1 Institute of Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Ludwig Institute for Cancer Research, Husargatan 3, Uppsala, S-75124, Sweden
2 Institute of Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Rudjer Boskovic Institute, Division of Molecular Medicine, Bijenicka 54, 10 000 Zagreb, Croatia
3 Institute of Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
4 Ludwig Institute for Cancer Research, Husargatan 3, Uppsala, S-75124, Sweden
5 NCI, Laboratory of Cellular Oncology, CCR, Bldg 37 Rm 4118, Bethesda, MD 20892, USA
6 Rudjer Boskovic Institute, Division of Molecular Medicine, Bijenicka 54, 10 000 Zagreb, Croatia
7 Department of Cell Biology, HHMI, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06510, USA
* Corresponding author. E-mail address: Ivan.Dikic{at}biochem2.de.
CIN85 is a multi-domain adaptor protein involved in Cbl-mediated down-regulation of epidermal growth factor (EGF) receptors. CIN85 SH3 domains specifically bind to a proline-arginine (PxxxPR) motif in Cbl, and this association appears to be important for EGF receptor endocytosis. Here we report identification of novel CIN85 effectors, all containing one or more PxxxPR motifs, that are indispensable for their mutual interactions. These effectors include phosphatidyl-inositol phosphatases SHIP-1 and synaptojanin 2B1, Arf GTPase activating proteins ASAP1 and ARAP3, adaptor proteins Hip1R and STAP1, and a Rho exchange factor p115Rho GEF. Acting as a molecular scaffold, CIN85 clusters its effectors and recruits them to high molecular weight complexes in cytosolic extracts of cells. Further characterization of CIN85 binding to ASAP1 revealed that formation of the complex is independent on cell stimulation. Overexpression of ASAP1 increased EGFR recycling, whereas ASAP1 containing mutated PxxxPR motif failed to promote this event. We propose that CIN85 functions as a scaffold molecule that binds to numerous endocytic accessory proteins, thus controlling distinct steps in trafficking of EGF receptors along the endocytic and recycling pathways.
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