title: Stroma-induced Jagged1 expression drives PC3 prostate cancer cell migration; disparate effects of RIP-generated proteolytic fragments on cell behaviour and Notch signaling.
abstract: The Notch ligand Jagged1 is subject to regulated intramembrane proteolysis (RIP) which yields a soluble ectodomain (sJag) and a soluble Jagged1 intracellular domain (JICD). The full-length Jagged1 protein enhances prostate cancer (PCa) cell proliferation and is highly expressed in metastatic cells. However, little is known regarding the mechanisms by which Jagged1 or its RIP-generated fragments might promote PCa bone metastasis. In the current study we show that bone marrow stroma (BMS) induces Jagged1 expression in bone metastatic prostate cancer PC3 cells and that this enhanced expression is mechanistically linked to the promotion of cell migration. We also show that RIP-generated Jagged1 fragments exert disparate effects on PC3 cell behaviour and Notch signaling. In conclusion, the expression of both the full-length ligand and its RIP-generated fragments must be considered in tandem when attempting to regulate Jagged1 as a possible PCa therapy.
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Electronic address: c.delury@lancaster.ac.uk.
authors.forename: Craig
authors.initials: C
authors.lastname: Delury
authors.affiliation: Genito Urinary Cancer Research Group, Institute of Cancer Sciences, Paterson Building, The University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4BX, UK. Electronic address: claire.hart@manchester.ac.uk.
authors.forename: Claire
authors.initials: C
authors.lastname: Hart
authors.affiliation: Genito Urinary Cancer Research Group, Institute of Cancer Sciences, Paterson Building, The University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4BX, UK. Electronic address: michael.brown@ics.manchester.ac.uk.
authors.forename: Mick
authors.initials: M
authors.lastname: Brown
authors.affiliation: Genito Urinary Cancer Research Group, Institute of Cancer Sciences, Paterson Building, The University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4BX, UK. Electronic address: noel.clarke@christie.nhs.uk.
authors.forename: Noel
authors.initials: N
authors.lastname: Clarke
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Electronic address: e.parkin@lancaster.ac.uk.
authors.forename: Edward
authors.initials: E
authors.lastname: Parkin
mesh_terms: D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059748:Proteolysis; D051880:Receptors, Notch / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D010446:Peptide Fragments; D051880:Receptors, Notch; D011994:Recombinant Proteins; D000072099:Serrate-Jagged Proteins
keywords: Invasion; Jagged1; Metastasis; Migration; Notch signaling; Prostate cancer