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Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases

Nature volume 404, pages 999–1003 (2000)Cite this article

Abstract

The Src family of protein tyrosine kinases (Src-PTKs) is important in the regulation of growth and differentiation of eukaryotic cells. The activity of Src-PTKs in cells of different types is negatively controlled by Csk, which specifically phosphorylates a conserved regulatory tyrosine residue at the carboxy-terminal tail of the Src-PTKs1,2,3. Csk is mainly cytoplasmic and Src-PTKs are predominantly membrane-associated. This raises a question about the mechanism of interaction between these enzymes. Here we present Cbp—a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the SH2 domain of Csk. Cbp is involved in the membrane localization of Csk and in the Csk-mediated inhibition of c-Src. In the plasma membrane Cbp is exclusively localized in the GM1 ganglioside-enriched detergent-insoluble membrane domain, which is important in receptor-mediated signalling4,5,6,7,8. These findings reveal Cbp as a new component of the regulatory mechanism controlling the activity of membrane-associated Src-PTKs.

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Figure 1: Csk association with the DIM-localized phosphoprotein.
Figure 2: Purification and structure of Cbp.
Figure 3: Characterization of Cbp protein.
Figure 4: Association and co-localization of Cbp with Csk in COS7 cells.
Figure 5: Overexpression of the Cbp suppresses the kinase activity of c-Src in COS7 cells.

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Acknowledgements

We thank Y. Yoshimura and S. Norioka for peptide sequence analysis; S. Yoshimura and S. Aimoto for peptide synthesis; K. Nakamura and H. Sabe for technical advice; Y. Takayama and T. Hirose for production of recombinamt Csk in Sf9 cells; and C. Schmedt for critical comments. This work was supported by the Ministry of Education, Science, Sports and Culture of Japan and the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research. A.T. was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemie.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Divisions of Protein Metabolism,

    Masahiro Kawabuchi, Katsuya Nagai & Masato Okada

  2. Organic Chemistry, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Yoshinori Satomi, Toshifumi Takao & Yasutsugu Shimonishi

  3. Department of Cell Membrane Biology Division of Biological Science, Institute of Scientific and Industrial Research Osaka University, 8-1 Mihogaoka, Ibaraki, 567-0047, Osaka, Japan

    Shigeyuki Nada

  4. Laboratory for Lymphocyte Signalling, Institute for Genetics, University of Cologne, Weyertal 121 , Cologne, D-50931, Germany

    Alexander Tarakhovsky

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  1. Masahiro Kawabuchi
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Correspondence to Alexander Tarakhovsky or Masato Okada.

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Kawabuchi, M., Satomi, Y., Takao, T. et al. Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404, 999–1003 (2000). https://doi.org/10.1038/35010121

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