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: Elena Rainero, Cristina Cianflone, Paolo Ettore Porporato, Federica Chianale, Valeria Malacarne, Valentina Bettio, Elisa Ruffo, Michele Ferrara, Fabio Benecchia, Daniela Capello, Wolfgang Paster, Irene Locatelli, Alessandra Bertoni, Nicoletta Filigheddu, Fabiola Sinigaglia, Jim C Norman, Gianluca Baldanzi, Andrea Graziani
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e97144 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24887021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL12
• Integrin beta1
• Diacylglycerol Kinase
• PKC-3 protein
• Protein Kinase C
• Matrix Metalloproteinase 9
• rac GTP-Binding Proteins

Topics

• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Chemokine CXCL12 (pharmacology)
• Diacylglycerol Kinase (metabolism)
• Female
• Humans
• Integrin beta1 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Neoplasm Invasiveness
• Protein Kinase C (metabolism)
• Protein Transport (drug effects)
• Pseudopodia (drug effects, metabolism)
• Signal Transduction (drug effects)
• rac GTP-Binding Proteins (metabolism)