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

被引:33
作者
Adams, M. N. [1 ]
Harrington, B. S. [1 ]
He, Y. [1 ]
Davies, C. M. [1 ,2 ]
Wallace, S. J. [2 ]
Chetty, N. P. [2 ]
Crandon, A. J. [2 ]
Oliveira, N. B. [2 ]
Shannon, C. M. [2 ]
Coward, J. I. [1 ,2 ]
Lumley, J. W. [3 ]
Perrin, L. C. [2 ]
Armes, J. E. [1 ,2 ]
Hooper, J. D. [1 ]
机构
[1] Univ Queensland, Translat Res Inst, Mater Res Inst, Brisbane, Qld 4102, Australia
[2] Mater Hlth Serv, South Brisbane, Qld, Australia
[3] Wesley Hosp, Auchenflower, Qld, Australia
基金
澳大利亚研究理事会;
关键词
DOMAIN-CONTAINING PROTEIN-1; CUB-DOMAIN; PKC-DELTA; SRC; RESISTANCE; SURVIVAL; IDENTIFICATION; METASTASIS; INVASION;
D O I
10.1038/onc.2014.88
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1375 / 1383
页数:9
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