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EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface

Oncogene volume 34, pages 1375–1383 (2015)Cite this article

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Abstract

Many cancers are dependent on inappropriate activation of epidermal growth factor receptor (EGFR), and drugs targeting this receptor can improve patient survival, although benefits are generally short-lived. We reveal a novel mechanism linking EGFR and the membrane-spanning, cancer-promoting protein CDCP1 (CUB domain-containing protein 1). Under basal conditions, cell surface CDCP1 constitutively internalizes and undergoes palmitoylation-dependent degradation by a mechanism in which it is palmitoylated in at least one of its four cytoplasmic cysteines. This mechanism is functional in vivo as CDCP1 is elevated and palmitoylated in high-grade serous ovarian tumors. Interestingly, activation of the EGFR system with EGF inhibits proteasome-mediated, palmitoylation-dependent degradation of CDCP1, promoting recycling of CDCP1 to the cell surface where it is available to mediate its procancer effects. We also show that mechanisms inducing relocalization of CDCP1 to the cell surface, including disruption of its palmitoylation and EGF treatment, promote cell migration. Our data provide the first evidence that the EGFR system can function to increase the lifespan of a protein and also promote its recycling to the cell surface. This information may be useful for understanding mechanisms of resistance to EGFR therapies and assist in the design of treatments for EGFR-dependent cancers.

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Acknowledgements

We thank Dr Jon Whitehead for helpful discussions. This work was supported by Cancer Council Queensland Grants 614205 and 1021827 and Wesley Research Institute Grant 2008/06 to JDH. MNA and BSH received Australian Post-Graduate Awards. JDH holds Australian Research Council Future Fellowship FT120100917.

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Authors and Affiliations

  1. Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia

    M N Adams, B S Harrington, Y He, C M Davies, J I Coward, J E Armes & J D Hooper

  2. Mater Health Services, South Brisbane, QLD, Australia

    C M Davies, S J Wallace, N P Chetty, A J Crandon, N B Oliveira, C M Shannon, J I Coward, L C Perrin & J E Armes

  3. Wesley Hospital, Auchenflower, QLD, Australia

    J W Lumley

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  1. M N Adams
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Correspondence to J D Hooper.

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Competing interests

JDH is an inventor on a patent describing CDCP1 as an anticancer target. All other authors declare no conflict of interest.

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Adams, M., Harrington, B., He, Y. et al. EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface. Oncogene 34, 1375–1383 (2015). https://doi.org/10.1038/onc.2014.88

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