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

Adams, M. N., Harrington, B. S., He, Y., Davies, C. M., Wallace, S. J., Chetty, N. P., Crandon, A. J., Oliveira, N. B., Shannon, C. M., Coward, J. I., Lumley, J. W., Perrin, L. C., Armes, J. E. and Hooper, J. D. (2015) EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface. Oncogene, 34 11: 1375-1383. doi:10.1038/onc.2014.88

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Author Adams, M. N.
Harrington, B. S.
He, Y.
Davies, C. M.
Wallace, S. J.
Chetty, N. P.
Crandon, A. J.
Oliveira, N. B.
Shannon, C. M.
Coward, J. I.
Lumley, J. W.
Perrin, L. C.
Armes, J. E.
Hooper, J. D.
Title EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
1476-5594
Publication date 2015
Year available 2014
Sub-type Article (original research)
DOI 10.1038/onc.2014.88
Open Access Status File (Author Post-print)
Volume 34
Issue 11
Start page 1375
End page 1383
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2015
Language eng
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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 31 March 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Official 2015 Collection
School of Medicine Publications
 
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