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

Adams, Mark N.; Harrington, Brittney S.; He, Yaowu; Davies, Claire; Wallace, Sarah; Chetty, Naven; Crandon, Alexander J.; Oliveira, Niara; Shannon, Catherine; Coward, Jermaine; Lumley, John W.; Perrin, Lewis; Armes, Jane E.; Hooper, John D.

doi:10.1038/onc.2014.88

Cited by 32 publications

(23 citation statements)

References 37 publications

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“…It was also reported that for some other proteins, their degradation depends on the S-acylation. For example, a cancer-promoting protein CDCP1 (CUB domain-containing protein 1) is degraded upon S-acylation, leading to a decrease of ovarian cancer cell migration (Adams et al, 2015). Therefore, it seems that S-acylation can play opposite roles in protein degradation.…”

Section: S-acylationmentioning

confidence: 99%

Progress toward Understanding Protein S-acylation: Prospective in Plants

2017

Front. Plant Sci.

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S-acylation, also known as S-palmitoylation or palmitoylation, is a reversible post-translational lipid modification in which long chain fatty acid, usually the 16-carbon palmitate, covalently attaches to a cysteine residue(s) throughout the protein via a thioester bond. It is involved in an array of important biological processes during growth and development, reproduction and stress responses in plant. S-acylation is a ubiquitous mechanism in eukaryotes catalyzed by a family of enzymes called Protein S-Acyl Transferases (PATs). Since the discovery of the first PAT in yeast in 2002 research in S-acylation has accelerated in the mammalian system and followed by in plant. However, it is still a difficult field to study due to the large number of PATs and even larger number of putative S-acylated substrate proteins they modify in each genome. This is coupled with drawbacks in the techniques used to study S-acylation, leading to the slower progress in this field compared to protein phosphorylation, for example. In this review we will summarize the discoveries made so far based on knowledge learnt from the characterization of protein S-acyltransferases and the S-acylated proteins, the interaction mechanisms between PAT and its specific substrate protein(s) in yeast and mammals. Research in protein S-acylation and PATs in plants will also be covered although this area is currently less well studied in yeast and mammalian systems.

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Section: S-acylationmentioning

confidence: 99%

Progress toward Understanding Protein S-acylation: Prospective in Plants

2017

Front. Plant Sci.

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“…3–9 CDCP1 expression is induced by hypoxia in clear-cell renal cell carcinoma (ccRCC) 10,11 and activated Ras in lung cancer, 12 and its localization at the membrane is induced by epidermal growth factor receptor in ovarian cancer. 13 The full-length, 135-kDa CDCP1 protein (flCDCP1) can be cleaved into a 70-kDa, membrane-bound cleaved CDCP1 (cCDCP1) and a 65-kDa portion that is shed on the extracellular side of the membrane. CDCP1 can be cleaved by plasmin, trypsin and matriptase, 8,14,15 and evidence is growing to support the necessity of CDCP1 cleavage for its activity.…”

Section: Introductionmentioning

confidence: 99%

CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer

et al. 2016

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Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks the estrogen, progesterone and HER2 receptors and is resistant to targeted and hormone therapies. TNBCs express high levels of the transmembrane glycoprotein, complement C1r/C1s, Uegf, Bmp1 (CUB)-domain containing protein 1 (CDCP1), which has been correlated with the aggressiveness and poor prognosis of multiple carcinomas. Full-length CDCP1 (flCDCP1) can be proteolytically cleaved, resulting in a cleaved membrane-bound isoform (cCDCP1). CDCP1 is phosphorylated by Src family kinases in its full-length and cleaved states, which is important for its pro-metastatic signaling. We observed that cCDCP1, compared with flCDCP1, induced a dramatic increase in phosphorylation of the migration-associated proteins: PKCδ, ERK1/2 and p38 mitogen-activated protein kinase in HEK 293T. In addition, only cCDCP1 induced migration of HEK 293T cells and rescued migration of the TNBC cell lines expressing short hairpin RNA against CDCP1. Importantly, we found that only cCDCP1 is capable of dimerization, which can be blocked by expression of the extracellular portion of cCDCP1 (ECC), indicating that dimerization occurs through CDCP1’s ectodomain. We found that ECC inhibited phosphorylation of PKCδ and migration of TNBC cells in two-dimensional culture. Furthermore, ECC decreased cell invasiveness, inhibited proliferation and stimulated apoptosis of TNBC cells in three-dimensional culture, indicating that the cCDCP1 dimer is an important contributor to TNBC aggressiveness. These studies have important implications for the development of a therapeutic to block CDCP1 activity and TNBC metastasis.

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“…Despite mRNA and protein levels increasing in response to WHF, the extent to which they did so differed, possibly due to post-transcriptional mechanisms that regulate CDCP1 expression [29, 30] or the localization of CDCP1 to poorly soluble cell membrane compartments [31]. These mechanisms might also differentially affect CDCP1 levels between cell lines.…”

Section: Discussionmentioning

confidence: 99%

CDCP1 is a novel marker of the most aggressive human triple-negative breast cancers

et al. 2016

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CDCP1, a transmembrane noncatalytic receptor, the expression of which has been associated with a poor prognosis in certain epithelial cancers, was found to be expressed in highly aggressive triple-negative breast cancer (TNBC) cell models, in which it promoted aggressive activities—ie, migration, invasion, anchorage-independent tumor growth, and the formation of vascular-like structures in vitro. By immunohistochemical (IHC) analysis of 100 human TNBC specimens, CDCP1 was overexpressed in 57% of samples, 38% of which exhibited a gain in CDCP1 copy number by fluorescence in situ hybridization (FISH). CDCP1 positivity was significantly associated between FISH and IHC. CDCP1 expression and gains in CDCP1 copy number synergized with nodal (N) status in determining disease-free and distant disease-free survival. The hazard ratios (HRs) of the synergies between CDCP1 positivity by IHC and FISH and lymph node positivity in predicting relapse did not differ significantly, indicating that CDCP1 overexpression in human primary TNBCs, regardless of being driven by gains in CDCP1, is for a critical factor in the progression of N-positive TNBCs. Thus, CDCP1 is a novel marker of the most aggressive N-positive TNBCs and a potential therapeutic target.

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

Cited by 32 publications

References 37 publications

Progress toward Understanding Protein S-acylation: Prospective in Plants

Progress toward Understanding Protein S-acylation: Prospective in Plants

CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer

CDCP1 is a novel marker of the most aggressive human triple-negative breast cancers

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