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Vol. 15, Issue 7, 3155-3166, July 2004
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#
* Institute of Biochemistry II, Goethe University Medical School, 60590 Frankfurt, Germany;
Ludwig Institute for Cancer Research, Uppsala S-75124, Sweden;
Rudjer Boskovic Institute, Division of Molecular Medicine, 10 000 Zagreb, Croatia;
|| National Cancer Institute, Laboratory of Cellular Oncology, Bethesda, Maryland 20892; and
¶ Department of Cell Biology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510
Submitted September 20, 2003;
Revised April 1, 2004;
Accepted April 5, 2004
Monitoring Editor: Jean Gruenberg
CIN85 is a multidomain adaptor protein involved in Cbl-mediated down-regulation of epidermal growth factor (EGF) receptors. CIN85 src homology 3 domains specifically bind to a proline-arginine (PxxxPR) motif in Cbl, and this association seems 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 EGF receptor 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.
These authors contributed equally to this work.
# Corresponding author. E-mail address: ivan.dikic{at}biochem2.de.
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