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Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors

Nature volume 416, pages 183–187 (2002)Cite this article

An Erratum to this article was published on 02 May 2002

Abstract

Cbl is a multi-adaptor protein involved in ligand-induced downregulation of receptor tyrosine kinases. It is thought that Cbl-mediated ubiquitination of active receptors is essential for receptor degradation and cessation of receptor-induced signal transduction1,2,3,4,5. Here we demonstrate that Cbl additionally regulates epidermal growth factor (EGF) receptor endocytosis. Cbl rapidly recruits CIN85 (Cbl-interacting protein of 85K; ref. 6) and endophilins (regulatory components of clathrin-coated vesicles7,8,9,10) to form a complex with activated EGF receptors, thus controlling receptor internalization. CIN85 was constitutively associated with endophilins, whereas CIN85 binding to the distal carboxy terminus of Cbl was increased on EGF stimulation. Inhibition of these interactions was sufficient to block EGF receptor internalization, delay receptor degradation and enhance EGF-induced gene transcription, without perturbing Cbl-directed receptor ubiquitination. Thus, the evolutionary divergent C terminus of Cbl uses a mechanism that is functionally separable from the ubiquitin ligase activity of Cbl to mediate ligand-dependent downregulation of receptor tyrosine kinases.

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Figure 1: CIN85 is recruited to Cbl–EGF receptor complexes on EGF stimulation.
Figure 2: CIN85 links endophilins with the Cbl–EGFR complex.
Figure 3: Effects of dominant interfering forms of CIN85 on Cbl-mediated ubiquitination, endocytosis and degradation of EGF receptors.
Figure 4: Role of CIN85 in the regulation of EGF-induced gene transcription.

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Acknowledgements

We thank S. Giordano and Y. Yarden for communication of unpublished results, and L. Claesson-Welsh and C.-H. Heldin for critical reading of the manuscript. We also thank other members of the Dikic laboratory for valuable comments and help with various reagents. This work was supported by a Marie Curie Fellowship of the European Community programme to P.S., and the Boehringer Ingelheim Fonds and the Swedish Strategic Funds to I.D.

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  1. Philippe Soubeyran, Katarzyna Kowanetz, Iwona Szymkiewicz and Wallace Y. Langdon: These authors contributed equally to this work

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S-75124, Sweden

    Philippe Soubeyran, Katarzyna Kowanetz, Iwona Szymkiewicz & Ivan Dikic

  2. Department of Pathology, University of Western Australia, 35 Stirling Highway, Crawley, 6009, Western Australia, Australia

    Wallace Y. Langdon

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  1. Philippe Soubeyran
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Correspondence to Ivan Dikic.

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Soubeyran, P., Kowanetz, K., Szymkiewicz, I. et al. Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature 416, 183–187 (2002). https://doi.org/10.1038/416183a

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