Dataset Information

The diacylglycerol kinase ?/atypical PKC/?1 integrin pathway in SDF-1? mammary carcinoma invasiveness.

ABSTRACT: Diacylglycerol kinase ? (DGK?), 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 DGK? activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of ?5?1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGK? mediates SDF-1?-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1? stimulation, DGK? is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1? induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGK? promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGK? by promoting Rac-mediated protrusion elongation and localized recruitment of ?1 integrin and MMP-9. We finally demonstrate that activation of DGK?, atypical PKCs signaling and ?1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1? induced DGK? - atypical PKC - ?1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells.

SUBMITTER: Rainero E

PROVIDER: S-EPMC4041662 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

The diacylglycerol kinase α/atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness.

Rainero Elena E Cianflone Cristina C Porporato Paolo Ettore PE Chianale Federica F Malacarne Valeria V Bettio Valentina V Ruffo Elisa E Ferrara Michele M Benecchia Fabio F Capello Daniela D Paster Wolfgang W Locatelli Irene I Bertoni Alessandra A Filigheddu Nicoletta N Sinigaglia Fabiola F Norman Jim C JC Baldanzi Gianluca G Graziani Andrea A

PloS one 20140602 6

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 ...[more]

PMID: 24887021

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Project description:BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is characterized by vascular endothelial damage caused by complement dysregulation. Consistently, complement inhibition therapies are highly effective in most patients with atypical hemolytic uremic syndrome. Recently, it was shown that a significant percentage of patients with early-onset atypical hemolytic uremic syndrome carry mutations in diacylglycerol kinase-?, an intracellular protein with no obvious role in complement. These data support an alternative, complement-independent mechanism leading to thrombotic microangiopathy that has implications for treatment of early-onset atypical hemolytic uremic syndrome. To get additional insights into this new form of atypical hemolytic uremic syndrome, the diacylglycerol kinase-? gene in a cohort with atypical hemolytic uremic syndrome was analyzed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Eighty-three patients with early-onset atypical hemolytic uremic syndrome (<2 years) enrolled in the Spanish atypical hemolytic uremic syndrome registry between 1999 and 2013 were screened for mutations in diacylglycerol kinase-?. These patients were also fully characterized for mutations in the genes encoding factor H, membrane cofactor protein, factor I, C3, factor B, and thrombomodulin CFHRs copy number variations and rearrangements, and antifactor H antibodies. RESULTS: Four patients carried mutations in diacylglycerol kinase-?, one p.H536Qfs*16 homozygote and three compound heterozygotes (p.W322*/p.P498R, two patients; p.Q248H/p.G484Gfs*10, one patient). Three patients also carried heterozygous mutations in thrombomodulin or C3. Extensive plasma infusions controlled atypical hemolytic uremic syndrome recurrences and prevented renal failure in the two patients with diacylglycerol kinase-? and thrombomodulin mutations. A positive response to plasma infusions and complement inhibition treatment was also observed in the patient with concurrent diacylglycerol kinase-? and C3 mutations. CONCLUSIONS: Data suggest that complement dysregulation influences the onset and disease severity in carriers of diacylglycerol kinase-? mutations and that treatments on the basis of plasma infusions and complement inhibition are potentially useful in patients with combined diacylglycerol kinase-? and complement mutations. A comprehensive understanding of the genetic component predisposing to atypical hemolytic uremic syndrome is, therefore, critical to guide an effective treatment.

Dataset Information

The diacylglycerol kinase ?/atypical PKC/?1 integrin pathway in SDF-1? mammary carcinoma invasiveness.

Publications

The diacylglycerol kinase α/atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness.

Similar Datasets

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