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c-Cbl is a critical modulator of the Ron tyrosine kinase receptor

Oncogene volume 22, pages 3669–3679 (2003)Cite this article

Abstract

Ron, the receptor tyrosine kinase (RTK) for the macrophage stimulating protein (MSP), activates multiple signaling pathways by recruiting several positive regulators to a multifunctional docking site. Here we show that stimulation by MSP also recruits a negative regulator, the c-Cbl ubiquitin ligase, to the multifunctional docking site as well as to a juxtamembrane tyrosine autophosphorylation site. c-Cbl recruitment to these two sites results in polyubiquitylation of Ron molecules, which are subsequently sorted for endocytosis and degradation. Both the phosphotyrosine binding domain of c-Cbl and its RING domain are essential for downregulation of Ron. Although Ron and c-Cbl are found also in physical complexes that include Grb2, these associations are insufficient for productive ubiquitylation of Ron. Our results shed light on the mechanism of receptor desensitization mediated by c-Cbl and its binding partner Grb2.

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Acknowledgements

This work was supported by grants from AIRC and COFIN-PRIN. LP was supported by EMBO fellowship ASTF 17.02.

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Authors and Affiliations

  1. Department of Medical Sciences, University of Piemonte Orientale, Novara, 28100, Italy

    Lorenza Penengo & Giovanni Gaudino

  2. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Chanan Rubin & Yosef Yarden

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  1. Lorenza Penengo
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  2. Chanan Rubin
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  3. Yosef Yarden
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  4. Giovanni Gaudino
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Correspondence to Giovanni Gaudino.

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Penengo, L., Rubin, C., Yarden, Y. et al. c-Cbl is a critical modulator of the Ron tyrosine kinase receptor. Oncogene 22, 3669–3679 (2003). https://doi.org/10.1038/sj.onc.1206585

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