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  • Original Paper
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Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor

Oncogene volume 20, pages 4058–4069 (2001)Cite this article

Abstract

The Cbl proto-oncogene product is tyrosine phosphorylated in response to a wide variety of stimuli. Cbl and the Abl nonreceptor tyrosine kinase both bind to SH3 domains from the SH2/SH3 adaptor Nck, and are candidate effectors for Nck function. Numerous additional SH2- and SH3-domain-mediated interactions are also possible between Cbl, Abl, and Nck. We find that these three signaling proteins associate when overexpressed in mammalian cells and can regulate each other's activity. Co-expression of wt Cbl together with c-Abl, the activity of which is normally repressed in vivo, led to extensive Abl-dependent phosphorylation of Cbl. The major proline-rich region of Cbl was required for its phosphorylation by c-Abl, but not by a constitutively activated Abl mutant, suggesting Cbl activates c-Abl by engaging its SH3 domain. Efficient phosphorylation of Cbl and its stable association with Abl required the SH2 domain of Abl, suggesting that SH2-phosphotyrosine interactions prevent dissociation of active Abl from Cbl. We also show that overexpression of Nck could repress the phosphorylation of Cbl by Abl in vivo. Studies with Nck mutants suggested that the Nck SH2 domain is responsible for inhibiting the activity of Abl toward both Cbl and Nck itself, most likely by competing with the Abl SH2 for tyrosine-phosphorylated binding sites.

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Acknowledgements

We thank MC Parrini and JJ Owen for critical reading of this manuscript; H Hanafusa, T Shishido, and AH Bouton for generously communicating results prior to publication; M Matsuda for monoclonal anti-GST antibody; and H Band for the human Cbl cDNA clone. T Miyoshi-Akiyama, CE Adler, and BJ Mayer were supported by the Howard Hughes Medical Institute. This work was supported in part by National Institutes of Health grant CA82258 to BJ Mayer.

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Author notes

  1. Tohru Miyoshi-Akiyama

    Present address: Department of Microbiology and Immunology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162, Japan

  2. Carolyn E Adler

    Present address: Department of Anatomy, University of California at San Francisco, San Francisco, 94143-0452, CA, USA

Authors and Affiliations

  1. Children's Hospital and Department of Microbiology and Molecular Genetics, Laboratory of Molecular Medicine, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, MA, USA

    Tohru Miyoshi-Akiyama, Lourdes M Aleman, Jodi M Smith, Carolyn E Adler & Bruce J Mayer

  2. Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, 06030-3301, Connecticut, CT, USA

    Lourdes M Aleman, Jodi M Smith & Bruce J Mayer

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Correspondence to Bruce J Mayer.

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Miyoshi-Akiyama, T., Aleman, L., Smith, J. et al. Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor. Oncogene 20, 4058–4069 (2001). https://doi.org/10.1038/sj.onc.1204528

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