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Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation

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Abstract

Cbl-b, a mammalian homolog of Cbl, consists of an N-terminal region (Cbl-b-N) highly homologous to oncogenic v-Cbl, a Ring finger, and a C-terminal region containing multiple proline-rich stretches and potential tyrosine phosphorylation sites. In the present study, we demonstrate that upon engagement of the T cell receptor (TCR), endogenous Cbl-b becomes rapidly tyrosine-phosphorylated. In heterogeneous COS-1 cells, Cbl-b was phosphorylated on tyrosine residues by both Syk- (Syk/Zap-70) and Src- (Fyn/Lck) family kinases, with Syk kinase inducing the most prominent effect. Syk associates and phosphorylates Cbl-b in Jurkat T cells. A Tyr-316 Cbl-binding site in Syk was required for the association with and for the maximal tyrosine phosphorylation of Cbl-b. Mutation at a loss-of-function site (Gly-298) in Cbl-b-N disrupts its interaction with Syk. Cbl-b constitutively binds Grb2 and becomes associated with Crk-L upon TCR stimulation. The Grb2- and the Crk-L-binding regions were mapped to the C-terminus of Cbl-b. The Crk-L-binding sites were further determined to be Y655DVP and Y709KIP, with the latter being the primary binding site. Taken together, these results implicate that Cbl-b is involved in TCR-mediated intracellular signaling pathways.

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Authors and Affiliations

  1. Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, 92121, California

    Chris Elly, Stephan Witte, Zhihong Zhang, Amnon Altman & Yun-Cai Liu

  2. Laboratory of Molecular Oncology, INSERM U119, Marseille, 13009, France

    Olivier Rosnet

  3. National Cancer Institute-Navy Medical Oncology Branch, Bethesda, 20899, Maryland, USA

    Stanley Lipkowitz

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  1. Chris Elly
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  2. Stephan Witte
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  3. Zhihong Zhang
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  4. Olivier Rosnet
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  5. Stanley Lipkowitz
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  6. Amnon Altman
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  7. Yun-Cai Liu
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Elly, C., Witte, S., Zhang, Z. et al. Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation. Oncogene 18, 1147–1156 (1999). https://doi.org/10.1038/sj.onc.1202411

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  • DOI: https://doi.org/10.1038/sj.onc.1202411

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