title: EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface.
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.
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
authors.forename: M N
authors.initials: MN
authors.lastname: Adams
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
authors.forename: B S
authors.initials: BS
authors.lastname: Harrington
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: 1] Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia [2] Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: C M
authors.initials: CM
authors.lastname: Davies
authors.affiliation: Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Wallace
authors.affiliation: Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: N P
authors.initials: NP
authors.lastname: Chetty
authors.affiliation: Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Crandon
authors.affiliation: Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: N B
authors.initials: NB
authors.lastname: Oliveira
authors.affiliation: Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: C M
authors.initials: CM
authors.lastname: Shannon
authors.affiliation: 1] Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia [2] Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: J I
authors.initials: JI
authors.lastname: Coward
authors.affiliation: Wesley Hospital, Auchenflower, QLD, Australia.
authors.forename: J W
authors.initials: JW
authors.lastname: Lumley
authors.affiliation: Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: L C
authors.initials: LC
authors.lastname: Perrin
authors.affiliation: 1] Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia [2] Mater Health Services, South Brisbane, QLD, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Armes
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
authors.forename: J D
authors.initials: JD
authors.lastname: Hooper
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D054878:Lipoylation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000473:pathology; D021381:Protein Transport; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; C508600:IL6 protein, human; D015850:Interleukin-6; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors