Mammalian Target of Rapamycin (mTOR) and S6 Kinase Down-regulate Phospholipase D2 Basal Expression and Function
| Autor: | Farnaz Tabatabaian, Kevin Dougherty, Mauricio Di Fulvio, Julian Gomez-Cambronero |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Neutrophils
Cellular differentiation HL-60 Cells P70-S6 Kinase 1 Protein Serine-Threonine Kinases Biology Biochemistry mTORC2 Gene Expression Regulation Enzymologic Chlorocebus aethiops Phospholipase D medicine Animals Humans Gene silencing Gene Silencing Molecular Biology PI3K/AKT/mTOR pathway Sirolimus Ribosomal Protein S6 Kinases TOR Serine-Threonine Kinases Interleukin-8 RPTOR Intracellular Signaling Peptides and Proteins Cell Differentiation Lipase Cell Biology Cell biology COS Cells Signal transduction medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 285:18991-19001 |
| ISSN: | 0021-9258 |
| Popis: | The mammalian target of rapamycin (mTOR) and S6 kinase (S6K) pathway is essential for cell differentiation, growth, and survival. Phospholipase D2 (PLD2) plays a key role in mTOR/S6K mitogenic signaling. However, the impact of PLD on mTOR/S6K gene expression is not known. Here we show that interleukin-8 (IL-8) increases mRNA expression levels for PLD2, mTOR, and S6K, with PLD2 preceding mTOR/S6K in time. Silencing of PLD2 gene expression abrogated IL-8-induced mTOR/S6K mRNA expression, whereas silencing of mTOR or S6K gene expression resulted in large (>3-fold and >5-fold, respectively) increased levels of PLD2 RNA, which was paralleled by increases in protein expression and lipase activity. Treatment of cells with 0.5 nm rapamycin induced a similar trend. These results suggest that, under basal conditions, PLD2 expression and concomitant activity is negatively regulated by the mTOR/S6K signaling pathway. Down-regulation of PLD2 was confirmed in differentiated HL-60 leukocytes overexpressing an mTOR-wild type, but not an mTOR kinase-dead construct. At the cellular level, overexpression of mTOR-wild type resulted in lower basal cell migration, which was reversed by treatment with IL-8. We propose that IL-8 reverses an mTOR/S6K-led down-regulation of PLD2 expression and enables PLD2 to fully function as a facilitator for cell migration. |
| Databáze: | OpenAIRE |
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