title: CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Wright
authors.affiliation: Department of Biomedical Engineering, University of California, Irvine, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Arulmoli
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Motazedi
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Nelson
authors.affiliation: Department of Pathology, Hoag Memorial Hospital Presbyterian, Newport Beach, CA, USA.
authors.forename: F S
authors.initials: FS
authors.lastname: Heinemann
authors.affiliation: Department of Biomedical Engineering, University of California, Irvine, CA, USA.|Department of Neurology, University of California, Irvine, CA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Flanagan
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
authors.forename: O V
authors.initials: OV
authors.lastname: Razorenova
mesh_terms: D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D000951:Antigens, Neoplasm; D017209:Apoptosis; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D048051:p38 Mitogen-Activated Protein Kinases