Temporal Production of the Signaling Lipid Phosphatidic Acid by Phospholipase D2 Determines the Output of Extracellular Signal-Regulated Kinase Signaling in Cancer Cells

Zhang, Feng; Wang, Ziqing; Lu, Maryia; Yonekubo, Yoshiya; Liang, Xiao; Zhang, Yueqiang; Wu, Ping; Zhou, Yong; Grinstein, Sergio; Hancock, John F.; Du, Guangwei

doi:10.1128/mcb.00987-13

Cited by 105 publications

(114 citation statements)

References 81 publications

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“…The limited number of animal studies that have been performed, however, suggest that both PLD1 and PLD2 play roles in tumor progression and that there will be many interesting stories to come in the context of primary cancer cell migration, inflammatory responses, and metabolic reprogramming. New techniques such as advanced intravital imaging, which can now be employed down to the subcellular level to examine tumor-stroma interactions (99), genetically encoded PA sensors (16,62), or in vivo cell tracking using MRI and single-photon emission computed tomography (100) will advance our understanding of the role of PLD1 in the early steps of tumor development and metastasis. Therapy resistance is one of the major challenges in treating cancer.…”

Section: Perspectivementioning

confidence: 99%

Cellular and Physiological Roles for Phospholipase D1 in Cancer

Zhang

Frohman

2014

Journal of Biological Chemistry

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Phospholipase D enzymes have long been proposed to play multiple cell biological roles in cancer. With the generation of phospholipase D1 (PLD1)-deficient mice and the development of small molecule PLD-specific inhibitors, in vivo roles for PLD1 in cancer are now being defined, both in the tumor cells and in the tumor environment. We review here tools now used to explore in vivo roles for PLD1 in cancer and summarize recent findings regarding functions in angiogenesis and metastasis. The phospholipase D (PLD)2 enzyme superfamily is defined by a conserved catalytic site and a functional commonality of transphosphatidylation activity at phosphodiester bonds found in a wide range of substrates. PLDs are present in bacteria and viruses as well as in yeast, plants, and animals. Classical PLD enzymes hydrolyze the abundant membrane lipid phosphatidylcholine to yield the second messenger phosphatidic acid (PA) and choline (1). Most vertebrates have two classic isoforms, PLD1 (2) and PLD2 (3), which are 50% identical in protein sequence in mammals and arose from a gene duplication event early in the vertebrate lineage. PLD2 is particularly intriguing in that it has a compact gene structure (4, 5) and resides within a 50-kb intron of another gene. Other animals, such as Drosophila melanogaster and Caenorhabditis elegans, have single PLD genes that are intermediate between mammalian PLD1 and PLD2 (1, 6, 7). PLD1 and PLD2 encode an identical series of protein regions, including Pleckstrin homology (PH) and Phox (PX) domains and a phosphatidylinositol 4,5-bisphospate-interacting motif that regulate association with specific subcellular membranes during signaling events, in addition to the pair of split catalytic domains (1). PLD function has been studied using biochemical, cell biological, and now physiological approaches. Potential roles for PLD in general or for PLD1 specifically have been reported in numerous physiological settings including ones relevant to cancer such as survival signaling (8 -11), control of cell polarity (12, 13), Ras activation (14 -19), and cell migration (13, 20 -26). Moreover, a PLD1 single nucleotide polymorphism (SNP) associates with the risk of non-small cell lung cancer and increased PLD1 expression and/or PLD activity have been reported in multiple types of cancer (27)(28)(29)(30)(31)(32)(33), although the mechanisms underlying this increase and the specific advantage this confers to the tumor cells are not known. As will be discussed as well, roles for PLD1 in the tumor microenvironment have also been uncovered, specifically in relationship to platelet activation (34 -36) and angiogenesis (22,26,37).In this review, we discuss physiological roles, in particular in the context of cancer, that have been identified for PLD1 using PLD lipase activity inhibitors and genetically modified animal models. Tools Used for Study of PLD FunctionCell biological roles for PLD enzymes have long been explored using a variety of types of inhibitors, the most popular of which has involved primary alcohols. Alt...

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Section: Perspectivementioning

confidence: 99%

Cellular and Physiological Roles for Phospholipase D1 in Cancer

Zhang

Frohman

2014

Journal of Biological Chemistry

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“…Liposomes for the binding assays were prepared as described previously (Zhang et al, 2014;Roach et al, 2012). 1,2-dioleoyl-sn-glycero-3-phosphocholine (PC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (PE), 1,2-dioleoyl-sn-glycero-3-phosphate (PA), 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol-3′-phosphate) (PI(3)P) and 1,2-dioleoyl-snglycero-3-phospho-(1′-myo-inositol-4′-phosphate) (PI(4)P) were purchased from Avanti Polar Lipids (Alabaster, AL).…”

Section: Liposome Pulldown Assaymentioning

confidence: 99%

The VPS34 PI3K negatively regulates RAB-5 during endosome maturation

Law

Seo

Wang

et al. 2017

Journal of Cell Science

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The GTPase Rab5 and phosphatidylinositol-3 phosphate [PI(3)P] coordinately regulate endosome trafficking. Rab5 recruits Vps34, the class III phosphoinositide 3-kinase (PI3K), to generate PI(3)P and recruit PI(3)P-binding proteins. Loss of Rab5 and loss of Vps34 have opposite effects on endosome size, suggesting that our understanding of how Rab5 and PI(3)P cooperate is incomplete. Here, we report a novel regulatory loop whereby Caenorhabditis elegans VPS-34 inactivates RAB-5 via recruitment of the TBC-2 Rab GTPase-activating protein. We found that loss of VPS-34 caused a phenotype with large late endosomes, as with loss of TBC-2, and that Rab5 activity (mice have two Rab5 isoforms, Rab5a and Rab5b) is increased in Vps34-knockout mouse embryonic fibroblasts (Vps34 is also known as PIK3C3 in mammals). We found that VPS-34 is required for TBC-2 endosome localization and that the pleckstrin homology (PH) domain of TBC-2 bound PI(3)P. Deletion of the PH domain enhanced TBC-2 localization to endosomes in a VPS-34-dependent manner. Thus, PI(3)P binding of the PH domain might be permissive for another PI(3)P-regulated interaction that recruits TBC-2 to endosomes. Therefore, VPS-34 recruits TBC-2 to endosomes to inactivate RAB-5 to ensure the directionality of endosome maturation.

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“…Liposomes were prepared as described previously (Roach et al, 2012;Zhang et al, 2014). 1,2-dioleoyl-sn-glycero-3-phosphocholine (PtdChl), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (PtdEth), 1,2-dioleoylsn-glycero-3-phosphate (PtdOH), 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol-3′-phosphate) [PI(3)P] and 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol-4′-phosphate) [PI(4)P] were from Avanti Polar Lipids (Alabaster, AL).…”

Section: Liposome Pulldown Assaymentioning

confidence: 99%

Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus

Jaber

Mohd-Naim

Wang

et al. 2016

Journal of Cell Science

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The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI (3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells to delineate whether Vps34 has additional roles in endocytic trafficking. In Vps34 −/− mouse embryonic fibroblasts (MEFs), transferrin recycling and EEA1 membrane localization were unaffected despite elevated Rab5-GTP levels. Strikingly, a large increase in Rab7-GTP levels, an accumulation of enlarged late endosomes, and decreased EGFR degradation were observed in Vps34-deficient cells. The hyperactivation of Rab7 in Vps34-deficient cells stemmed from the failure to recruit the Rab7 GTPase-activating protein (GAP) Armus (also known as TBC1D2), which binds to PI(3)P, to late endosomes. Protein-lipid overlay and liposome-binding assays reveal that the putative pleckstrin homology (PH) domain in Armus can directly bind to PI(3)P. Elevated Rab7-GTP led to the failure of intraluminal vesicle (ILV) formation and lysosomal maturation. Rab7 silencing and Armus overexpression alleviated the vacuolization seen in Vps34-deficient cells. Taken together, these results demonstrate that Vps34 has a previously unknown role in regulating Rab7 activity and late endosomal trafficking.

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Temporal Production of the Signaling Lipid Phosphatidic Acid by Phospholipase D2 Determines the Output of Extracellular Signal-Regulated Kinase Signaling in Cancer Cells

Cited by 105 publications

References 81 publications

Cellular and Physiological Roles for Phospholipase D1 in Cancer

Cellular and Physiological Roles for Phospholipase D1 in Cancer

The VPS34 PI3K negatively regulates RAB-5 during endosome maturation

Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus

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