Phospholipase D and Its Product, Phosphatidic Acid, Mediate Agonist-dependent Raf-1 Translocation to the Plasma Membrane and the Activation of the Mitogen-activated Protein Kinase Pathway

Rizzo, Mark A.; Shome, Kuntala; Vasudevan, Chandrasekaran; Stolz, Donna B.; Sung, Tsung-Chang; Frohman, Michael A.; Watkins, Simon C.; Romero, Guillermo

doi:10.1074/jbc.274.2.1131

Cited by 280 publications

(282 citation statements)

References 53 publications

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“…Overexpressed PLD2 has been demonstrated in the plasma membrane as well as intracellular vesicles and the nucleus (18,64,67). Like PLD1, PLD2 has been demonstrated to undergo agonist-induced translocation between membrane compartments (25,67,71,72).…”

Section: Discussionmentioning

confidence: 99%

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Barton¹,

Bourgoin²,

Kusner

2004

The Journal of Immunology

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Phagocytosis is a fundamental feature of the innate immune system, required for antimicrobial defense, resolution of inflammation, and tissue remodeling. Furthermore, phagocytosis is coupled to a diverse range of cytotoxic effector mechanisms, including the respiratory burst, secretion of inflammatory mediators and Ag presentation. Phospholipase D (PLD) has been linked to the regulation of phagocytosis and subsequent effector responses, but the identity of the PLD isoform(s) involved and the molecular mechanisms of activation are unknown. We used primary human macrophages and human THP-1 promonocytes to characterize the role of PLD in phagocytosis. Macrophages, THP-1 cells, and other human myelomonocytic cells expressed both PLD1 and PLD2 proteins. Phagocytosis of complement-opsonized zymosan was associated with stimulation of the activity of both PLD1 and PLD2, as demonstrated by a novel immunoprecipitation-in vitro PLD assay. Transfection of dominant-negative PLD1 or PLD2 each inhibited the extent of phagocytosis (by 55–65%), and their combined effects were additive (reduction of 91%). PLD1 and PLD2 exhibited distinct localizations in resting macrophages and those undergoing phagocytosis, and only PLD1 localized to the phagosome membrane. The COS-7 monkey fibroblast cell line, which has been used as a heterologous system for the analysis of receptor-mediated phagocytosis, expressed PLD2 but not PLD1. These data support a model in which macrophage phagocytosis is coordinately regulated by both PLD1 and PLD2, with isoform-specific localization. Human myelomonocytic cell lines accurately model PLD-dependent signal transduction events required for phagocytosis, but the heterologous COS cell system does not.

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Section: Discussionmentioning

confidence: 99%

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Barton¹,

Bourgoin²,

Kusner

2004

The Journal of Immunology

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“…Downstream targets of PA have been described including phosphatidylinositol-4-phosphate-5-kinase (Moritz et al, 1992;Jenkins et al, 1994) and Raf (Ghosh et al, 1996;Rizzo et al, 1999). While impacting upon Raf activation may certainly contribute to the mitogenic properties of PLD, the ability of PLD to suppress cell cycle arrest and overcome apoptosis (Joseph et al, 2002) suggests that PLD is providing a survival signal not usually attributed to Raf.…”

Section: Suppression Of Pld Activity In Mda-mb-231 Cells Confers Sensmentioning

confidence: 99%

Phospholipase D confers rapamycin resistance in human breast cancer cells

2003

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mTOR (mammalian target of rapamycin) is a protein kinase that regulates cell cycle progression and cell growth. Rapamycin is a highly specific inhibitor of mTOR in clinical trials for the treatment of breast and other cancers. mTOR signaling was reported to require phosphatidic acid (PA), the metabolic product of phospholipase D (PLD). PLD, like mTOR, has been implicated in survival signaling and the regulation of cell cycle progression. PLD activity is frequently elevated in breast cancer. We have investigated the effect of rapamycin on breast cancer cell lines with different levels of PLD activity. MCF-7 cells, with relatively low levels of PLD activity, were highly sensitive to the growth-arresting effects of rapamycin, whereas MDA-MB-231 cells, with a 10-fold higher PLD activity than MCF-7 cells, were highly resistant to rapamycin. Elevating PLD activity in MCF-7 cells led to rapamycin resistance; and inhibition of PLD activity in MDA-MB-231 cells increased rapamycin sensitivity. Elevated PLD activity in MCF-7 cells also caused rapamycin resistance for S6 kinase phosphorylation and serum-induced Myc expression. These data implicate mTOR as a critical target for survival signals generated by PLD and suggest that PLD levels in breast cancer could be a valuable indicator of the likely efficacy of rapamycin treatment.

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“…12,13 It is interesting to note that mediation of plasma membrane translocation of the Ras effector Raf-1 by PA has also been demonstrated. 14 Thus, the membrane recruitment function of PA could serve to bring an activator and an effector of Ras into proximity, thereby maximizing the efficiency of signal transduction. Although PLD activity is stimulated by ligands, such as mitogens, growth factors or cytokines, the long-term effect of PLD activation on PLD expression is unknown.…”

mentioning

confidence: 99%

Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

Kang

Park

Kim

et al. 2010

Intl Journal of Cancer

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Phospholipase D (PLD) is an important signaling enzyme implicated in the control of many biological processes, including cell proliferation and survival. Despite the importance of the duration and amplitude of PLD signaling in carcinogenesis, mechanisms that regulate PLD expression remain poorly understood. In our study, we define the regulatory components of the machinery that specifies selective PLD1 induction via signals propagated through PLD activity. We demonstrate for the first time that establishment of a positive feedback loop that is dependent on enzymatic activity originating from both PLD1 and PLD2 isozymes enhances selective expression of PLD1, but not PLD2. Phosphatidic acid, the product of PLD activity, leads to an increase in the Ras-ERK/PI3K-NFjB signaling cascade and enhances binding of NFjB to the PLD1 promoter, consequently inducing selective PLD1 expression in SK-BR3 breast cancer cells. Moreover, selective PLD inhibitor suppressed epidermal growth factor-induced matrix metalloproteinase upregulation and invasion by inhibiting PLD1 expression. In conclusion, we propose that autoregulation of PLD activity might be coupled to induction of PLD1 expression, and thereby play a role in carcinogenesis.Phosphatidic acid (PA) has emerged as an important mediator of lipid signaling that is associated with regulation of cell growth and proliferation, membrane trafficking and cytoskeletal reorganization. Because of its regulatory role, the level of PA itself should be tightly regulated through synthesis and turnover. PA is the product of phosphatidylcholine hydrolysis catalyzed by phospholipase D (PLD) and is strategically located at the intersection of several major signaling and metabolic pathways. Endogenous levels of PA are low in resting cells, and PLD activity is tightly regulated by mechanisms that control secretion, migration, survival and proliferation of cells. 1,2 PLD is activated by a variety of mitogens, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and interleukin 1b (IL-1b), [3][4][5][6][7] and its involvement in many cellular biological processes, including cell proliferation, survival, vesicular trafficking and secretion, has been demonstrated. 1,8 Two distinct isoforms of mammalian PLD, PLD1 and PLD2, have been identified. 9 PLD mediates the parallel reactions of phospholipid hydrolysis and transphosphatidylation. Primary alcohols, such as ethanol or 1-butanol, serve as competitive nucleophiles to water, resulting in a transphosphatidylation reaction that produces a phosphatidylalcohol, such as phosphatidylbutanol (PtdBut), instead of PA. Thus, primary alcohols have been used almost exclusively as the only means of preventing PA production for study of the role of PLD-mediated PA formation in certain cellular processes. 10 Potent dual PLD1 and PLD2 inhibitors, as well as isoformselective PLD inhibitors, with considerable pharmacological characterization have recently been developed. 11 Recent work has demonstrated a novel PA target in the Ras/Raf/ERK si...

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Phospholipase D and Its Product, Phosphatidic Acid, Mediate Agonist-dependent Raf-1 Translocation to the Plasma Membrane and the Activation of the Mitogen-activated Protein Kinase Pathway

Cited by 280 publications

References 53 publications

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Phospholipase D confers rapamycin resistance in human breast cancer cells

Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

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