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Cbl as a Master Regulator of Receptor Tyrosine Kinase Trafficking

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Vesicle Trafficking in Cancer

Abstract

The Cbl proteins are a family of RING finger ubiquitin ligases which are found throughout metazoans. In mammalian cells there are three Cbl proteins, Cbl, Cbl-b, and Cbl-c. The RING finger domain, responsible for ubiquitin ligase activity, is surrounded by protein interaction motifs that allow Cbl proteins to interact with a large number of signaling proteins and thus function in many signaling pathways. Receptor tyrosine kinases (RTKs) are rapidly internalized upon activation and can either be recycled to the cell surface or degraded in the lysosome (a process known as downregulation). The Cbl proteins ubiquitinate the activated RTKs and mediate their trafficking to the lysosome for degradation. Thus, they are critical regulators of RTK downregulation. This process is tightly regulated by RTK-mediated phosphorylation of the Cbl proteins that activates the ubiquitin ligase activity of the Cbl protein. In addition, multiple proteins can attenuate Cbl-mediated ubiquitination and downregulation of the RTK. Mutations which disrupt the ubiquitin ligase activity of the Cbl proteins result in oncogenic forms, and such mutations have been described in human myeloid neoplasms. In addition mutations in the RTK or overexpression of negative regulators of Cbl proteins can result in aberrant RTK downregulation and transformation. Thus, the Cbl proteins are critical regulators of RTK trafficking and serve to tune the level of RTK activity.

Ke Ma and Stephen C. Kales contributed equally to this work.

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Acknowledgement

Financial Support: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research

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  1. Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 2066, 37 Convent Drive, Bethesda, MD, 20892, USA

    Ke Ma, Stephen C. Kales, Marion M. Nau & Stanley Lipkowitz

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Correspondence to Stanley Lipkowitz .

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    Yosef Yarden

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Ma, K., Kales, S.C., Nau, M.M., Lipkowitz, S. (2013). Cbl as a Master Regulator of Receptor Tyrosine Kinase Trafficking. In: Yarden, Y., Tarcic, G. (eds) Vesicle Trafficking in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6528-7_11

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