title: The diacylglycerol kinase α/atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness.
abstract: Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells.
authors.affiliation: Integrin Biology Laboratory, Beatson Institute for Cancer Research, Glasgow, Scotland, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Rainero
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cianflone
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Paolo Ettore
authors.initials: PE
authors.lastname: Porporato
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Chianale
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Malacarne
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bettio
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ruffo
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ferrara
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benecchia
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Paster
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Locatelli
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bertoni
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Filigheddu
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Sinigaglia
authors.affiliation: Integrin Biology Laboratory, Beatson Institute for Cancer Research, Glasgow, Scotland, United Kingdom.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.affiliation: Integrin Biology Laboratory, Beatson Institute for Cancer Research, Glasgow, Scotland, United Kingdom.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Baldanzi
authors.affiliation: Integrin Biology Laboratory, Beatson Institute for Cancer Research, Glasgow, Scotland, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Graziani
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D019012:Integrin beta1; D019852:Diacylglycerol Kinase; C115015:PKC-3 protein; D011493:Protein Kinase C; D020780:Matrix Metalloproteinase 9; D020744:rac GTP-Binding Proteins