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Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule βPix

Oncogene volume 25, pages 3071–3078 (2006)Cite this article

Abstract

The Pix/Cool proteins are involved in the regulation of cell morphology by binding to small Rho GTPases and kinases of the Pak family. Recently, it has been shown that βPix/Cool-1 associates with the ubiquitin ligase Cbl, which appears to be a critical step in Cdc42-mediated inhibition of epidermal-growth-factor-receptor (EGFR) ubiquitylation and downregulation. Here we show that the SH3 domain of βPix specifically interacts with a proline–arginine motif (PxxxPR) present within the ubiquitin ligase Cbl and Pak1 kinase. Owing to targeting of the same sequence, Cbl and Pak1 compete for binding to βPix. In this complex, Cbl mediates ubiquitylation and subsequent degradation of βPix. Our findings reveal a double feedback loop in which the Cdc42/βPix complex blocks Cbl's ability to downregulate EGFR, while Cbl in turn promotes degradation of βPix in order to escape this inhibition. Such a relationship provides a mechanism to fine-tune the kinetics of RTK endocytosis and degradation depending on the pool of active Cdc42 and the duration of EGFR signaling.

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Acknowledgements

We thank Richard Cerione for providing the βPix/Cool-1 construct and Hoi Young Lee for the βPix-specific siRNA vector. This work was supported by the Deutsche Forschungsgemeinschaft (DI 931/1-2). MHHS is a fellow of the European Molecular Biology Organization (EMBO, ALTF 881-2003).

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Author notes

  1. I Szymkiewicz

    Present address: Dr I Szymkiewicz, Serono International SA, 15bis Chemin Des Mines, Geneva, Switzerland

  2. M H H Schmidt and K Husnjak: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biochemistry II, University Hospital of the Johann Wolfgang Goethe University, Frankfurt am Main, Germany

    M H H Schmidt, K Husnjak, K Haglund & I Dikic

  2. Division of Molecular Medicine, Laboratory of Molecular Oncology, Rudjer Boskovic Institute, Zagreb, Croatia

    K Husnjak

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  1. M H H Schmidt
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Correspondence to I Dikic.

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Schmidt, M., Husnjak, K., Szymkiewicz, I. et al. Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule βPix. Oncogene 25, 3071–3078 (2006). https://doi.org/10.1038/sj.onc.1209329

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