Journal Article

The Diacylglycerol Kinase α/Atypical PKC/β1 Integrin Pathway in SDF-1α Mammary Carcinoma Invasiveness

Filigheddu, Nicoletta, Malacarne, Valeria, Bettio, Valentina, Baldanzi, Gianluca, Cianflone, Cristina, Benecchia, Fabio, Graziani, Andrea, Norman, Jim C., Bertoni, Alessandra, Ruffo, Elisa, Porporato, Paolo Ettore, Chianale, Federica, Capello, Daniela, Locatelli, Irene, Rainero, Elena, Ferrara, Michele, Paster, Wolfgang, Sinigaglia, Fabiola

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acids / Activation / Biology / Biology and life sciences / Bone marrow / Breast cancer / Breast carcinoma / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Carcinoma / Cell adhesion & migration / Cell Line, Tumor / Cell migration / Chemokine CXCL12 - pharmacology / Chemokines / Cytoskeleton / Diacylglycerol kinase / Diacylglycerol Kinase - metabolism / Elongation / Epidermal growth factor / Epithelial cells / Female / Gelatinase B / Humans / Integrin beta1 - metabolism / Invasiveness / Kinases / Laboratories / Leukemia / Localization / Mammary gland / Matrix Metalloproteinase 9 - metabolism / Medical prognosis / Medical research / Medicine / Medicine and Health Sciences / Metalloproteinase / Metastasis / Neoplasm Invasiveness / Phosphatidic acid / Protein kinase C / Protein Kinase C - metabolism / Protein Transport - drug effects / Proteins / Pseudopodia - drug effects / Pseudopodia - metabolism / rac GTP-Binding Proteins - metabolism / Secretion / Signal transduction / Signal Transduction - drug effects / Signaling / Tumors