The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (And a surprise discovery: PLD2 is a GEF)

Gómez‐Cambronero, Julian

doi:10.1016/j.cellsig.2011.06.017

Cited by 33 publications

(35 citation statements)

References 210 publications

(227 reference statements)

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“…Locati et al (2001) reported that PLD can be selectively induced in pathogen-activated human monocytes. Sphingosine 1-phosphate (S1P)-induced PLD activation is reported to regulate IL-8 secretion via a Gi protein/PKC/PLD pathway and PLD is involved in S1P-induced ERK activation and IL-8 secretion in bronchial epithelial cells Gomez-Cambronero, 2011;Brandenburg et al, 2014). Overexpression of catalytically inactive mutants of PLD attenuates LPA-induced IL-13Ralpha2 gene expression and protein secretion (Zhao et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells

Koo

Han

2016

J. Toxicol. Sci.

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-Cigarette smoking is known to be associated with various kinds of diseases, including atherosclerotic cardiovascular disease, cancer, and chronic obstructive pulmonary disease (COPD). Many of the diseases associated with cigarette smoking are also associated with changes in interleukin-6 (IL-6) expression. In this study, we investigated the role of phospholipase D1 (PLD1) in IL-6 expression induced by cigarette smoke extract (CSE). Treatment with CSE increased PLD1 and IL-6 expressions in human bronchial epithelial (BEAS-2B) cells. In addition, CSE treatment activated PLC, PKC, and MAPK pathway through the Gi protein-coupled receptor. Pertussis toxin (PTX, Gi protein-coupled receptor inhibitor), PAO (PLC inhibitor), Go6976 (PKC inhibitor) and SB203580 (p38MAPK inhibitor) decreased CSEinduced PLD1 expression. The results show that Gi protein, PLC, PKC, and p38MAPK act as upstream regulators of PLD1 in CSE-treated BEAS-2B cells. Moreover, PLD1 siRNA transfection decreased CSEinduced ATF2 phosphorylation and IL-6 expression. In addition, inhibitors of Gi protein, PLC, PKC, and p38MAPK, and ATF2 siRNA transfection decreased CSE-induced IL-6 expression, suggesting that CSEinduced IL-6 expression is regulated via Gi protein/PLC/PKC/p38MAPK/PLD1/ATF2 pathway. Taken together, the results suggest that PLD1 is an important regulator of IL-6 expression induced by CSE in BEAS-2B cells.

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Section: Introductionmentioning

confidence: 99%

Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells

Koo

Han

2016

J. Toxicol. Sci.

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“…In a recent study, we reported for the first time that phospholipase D2 (PLD2) acts as a GEF for the Rac2 GTPase, which is a novel characterization of a dual activity enzyme with both lipase and GEF activities embedded in the same protein (Gomez-Cambronero, 2011;Mahankali et al, 2011b). PLD2 has a phox homology (PX) domain, a pleckstrin homology (PH) domain and two HKD catalytic domains.…”

Section: Introductionmentioning

confidence: 99%

“…PLD2 has a phox homology (PX) domain, a pleckstrin homology (PH) domain and two HKD catalytic domains. HKD domains mediate lipase activity, while the GEF activity site resides in the PX domain and is assisted by the PH domain (Gomez-Cambronero, 2011;Mahankali et al, 2011b).…”

Section: Introductionmentioning

confidence: 99%

A GEF-to-phospholipase molecular switch caused by PA, RAC and jak tyrosine kinase, that explains leukocyte cell migration

Mahankali

Henkels

Gómez‐Cambronero

2013

Journal of Cell Science

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SummaryPhospholipase D2 (PLD2) is a cell-signaling molecule that bears two activities: a guanine-nucleotide exchange factor (GEF) and a lipase that reside in the PX/PH domains and in two HKD domains, respectively. Upon cell stimulation, the GEF activity yields Rac2-GTP and the lipase activity yields phosphatidic acid (PA). In the present study, we show for the first time that these activities regulate one another. Upon cell stimulation, both GEF and lipase activities are quickly (within ,3 min) elevated. As soon as it is produced, PA positively feeds back on the GEF and further activates it. Rac2-GTP, on the other hand, is inhibitory to the lipase activity. PLD2 would remain downregulated if it were not for the contribution of the tyrosine kinase Janus kinase 3 (JAK3), which restores lipase action (by phosphorylation at Y415). Conversely, the GEF is inhibited upon phosphorylation by JAK3 and is effectively terminated by this action and by the increasing accumulation of PA at .15 min of cell stimulation. This PA interferes with the ability of the GEF to bind to its substrate (Rac2-GTP). Thus, both temporal inter-regulation and phosphorylation-dependent mechanisms are involved in determining a GEF-lipase switch within the same molecule. Human neutrophils stimulated by interleukin-8 follow a biphasic pattern of GEF and lipase activation that can be explained by such an intramolecular switch. This is the first report of a temporal inter-regulation of two enzymatic activities that reside in the same molecule with profound biological consequences in leukocyte cell migration.

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“…Apart from generating one of the major lipid second messengers, PA, PLD interacts with a large number of protein partners, some of which are directly related to the actin cytoskeleton, which is involved with the protein machinery responsible for cell adhesion and migration (18). Precisely for this role, certain pathologies that rely on cell migration, such as cancer metastasis, have put PLD at center stage in cancer research.…”

Section: Pldmentioning

confidence: 99%

Thematic Minireview Series on Phospholipase D and Cancer

Gómez‐Cambronero

Carman

2014

Journal of Biological Chemistry

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Phospholipase D (PLD) signaling plays a critical role in cell growth and proliferation, vesicular trafficking, secretion, and endocytosis. At the cellular level, PLD and its reaction product, phosphatidate, interact with a large number of protein partners that are directly related to the actin cytoskeleton and cell migration. Cancer invasion and metastasis rely heavily on cellular motility, and as such, they have put PLD at center stage in cancer research. This minireview series highlights some of the molecular mechanisms that provide evidence for the emerging tumorigenic potential of PLD, the role of the microenvironment, and putative connections with inflammation. PLD represents a potential target for the rational development of therapeutics against cancer and other diseases. PLD3 catalyzes the conversion of phosphatidylcholine to PA and choline. The enzyme reaction was first identified from carrots in 1947 by Hanahan and Chaikoff (1, 2), and indeed, most of the early work on the biochemistry of PLD was performed with the enzyme from plants (3). The existence of PLD in mammals was not discovered until 1973 (4). From the mid-1980s to the early 1990s, it became apparent that PLD played a major role in lipid signaling by generating PA, which was then converted to diacylglycerol for the activation of PKC (5). Interest in PLD intensified with the observations that PA itself governed several physiological processes that include cell growth and proliferation, vesicular trafficking, secretion, and endocytosis (6 -12).Studies on PLD were challenged with serious difficulties due to limited knowledge of its regulation on a molecular level, as well as the difficulty of purifying the enzyme from natural sources. However, the PLD field received a strong boost in 1994 when Wang et al. (13) identified the PLD gene from castor bean. This seminal contribution led to the identifications of orthologous genes from yeast (14) and mammals (15-17). The field also expanded when the action of PLD was implicated in Parkinson and Alzheimer diseases, as well as in several cancers.Apart from generating one of the major lipid second messengers, PA, PLD interacts with a large number of protein partners, some of which are directly related to the actin cytoskeleton, which is involved with the protein machinery responsible for cell adhesion and migration (18). Precisely for this role, certain pathologies that rely on cell migration, such as cancer metastasis, have put PLD at center stage in cancer research. High levels of PLD activity are reported in a variety of cancers, such as breast, gastric, colorectal, and lung (19 -22) cancers. Further, radiation in combination with PLD inhibition (specific for both PLD1 and PLD2) has been shown to be an efficient way to improve radiosensitivity of breast cancer cell lines and in animal models (23)(24)(25)(26).Recent studies with animal models have indicated that PLD is integral to breast cancer progression by increasing tumor growth and cell invasion (27-29). Significant expansion of the PLD field is e...

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The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (And a surprise discovery: PLD2 is a GEF)

Cited by 33 publications

References 210 publications

Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells

Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells

A GEF-to-phospholipase molecular switch caused by PA, RAC and jak tyrosine kinase, that explains leukocyte cell migration

Thematic Minireview Series on Phospholipase D and Cancer

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