Abstract
The mammalian proto-oncogene Cbl and its cellular homologues in Caenorhabditis elegans (Sli-1) and Drosophila (D-Cbl) are negative regulators of some growth factor receptor signaling pathways. Herein we show that Cbl can negatively regulate another signaling molecule, namely theSrc-family kinase Hck by targeting it for degradation. Hck-mediated cellular transformation of murine fibroblasts is reverted by ectopic expression of a membrane-anchored allele of Cbl as assessed by the cellular morphology, suppression of anchorage independent growth, and an overall reduction in the total tyrosine phosphorylation levels within the cells. The expression of Cbl at the plasma membrane targets both Hck and itself for ubiquitination and degradation, requiring an intact RING finger. Pharmacological inhibition of the proteasome prevents the degradation of Hck correlating with an increase in the phosphotyrosine levels within the cells. Activated Hck and membrane-anchored Cbl are present in similar subcellular localizations and co-immunoprecipitate, suggesting that their interaction is required for subsequent ubiquitination and degradation. Interestingly, both constitutively active and kinase-inactive Hck interact with and are targeted for degradation by Cbl. This work illustrates alternate means to regulate Src-family kinases, and suggests that Cbl may be able to suppress many signaling pathways that are activated in various proliferative syndromes including cancer.
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Acknowledgements
We would like to thank the members of the lab for their constructive comments and discussions during the course of this work. We would also like to thank W Langdon, T Hunter and HC Cheng for valuable reagents used in this study. This work was supported by grants from the Canadian Institutes of Health Research and the Cancer Research Society (CRS) of Canada to SM Robbins. CJ Howlett is supported by an Alberta Heritage for Medical Research (AHFMR) Studentship and SM Robbins is a senior scholar of the AHFMR and holds a Canada Research Chair in Cancer Biology.
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Howlett, C., Robbins, S. Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation. Oncogene 21, 1707–1716 (2002). https://doi.org/10.1038/sj.onc.1205228
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DOI: https://doi.org/10.1038/sj.onc.1205228
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