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Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells

Oncogene volume 21, pages 1423–1433 (2002)Cite this article

Abstract

CBL and the related CBL-B protein are two members of a family of RING finger type ubiquitin E3 ligases that are believed to function as negative regulators of signal transduction in hematopoietic and immune cells. In mice, expression of v-Cbl causes lymphomas, and targeted disruption of either the CBL gene or the CBL-B gene can result in a lymphoproliferative disorder or hypersensitivity of lymphocytes. CBL is one of the most prominent targets of the BCR/ABL tyrosine kinase oncogene. We compared the role of CBL and CBL-B in signal transduction of BCR/ABL using pairs of cell lines before and after expression of BCR/ABL. In contrast to CBL, BCR/ABL was found to rapidly downregulate the expression of CBL-B protein. The decrease in CBL-B protein induced by BCR/ABL was associated with downregulation of CBL-B mRNA. Downregulation and tyrosine phosphorylation of CBL-B required BCR/ABL kinase activity. However, despite their known similarities in structure and function, we found CBL and CBL-B proteins to be involved in distinct signaling complexes. CBL was predominantly in a complex with phosphatidylinositol 3′-kinase and CRKL, while CBL-B was not associated with any significant phosphatidylinositol 3′-kinase activity. A major CBL-B associated protein was identified as mono-ubiquitinated Vav, a nucleotide exchange factor for Rac1. These results demonstrate that BCR/ABL signals differentially through CBL and CBL-B, with downregulation of the CBL-B protein potentially contributing to BCR/ABL-mediated transformation.

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Acknowledgements

This work was supported by the Leukemia Research Foundation (M Sattler), and National Institute of Health grants CA78348 (R Salgia) and DK50654 (JD Griffin).

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Authors and Affiliations

  1. Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, MA, USA

    Martin Sattler, Yuri B Pride, Laura R Quinnan, Shalini Verma, Nicole A Malouf, Hervé Husson, Ravi Salgia & James D Griffin

  2. Genetics Department, Medicine Branch, National Cancer Institute, National Naval Medical Center, Bethesda, 20889, Maryland, MD, USA

    Stanley Lipkowitz

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  1. Martin Sattler
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  2. Yuri B Pride
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Correspondence to Martin Sattler.

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Sattler, M., Pride, Y., Quinnan, L. et al. Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells. Oncogene 21, 1423–1433 (2002). https://doi.org/10.1038/sj.onc.1205202

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