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PLD2 (phospholipase D2)

Written2013-04Chang Sup Lee, Sung Ho Ryu
Department of Life Science, Division of Molecular, Life Sciences, Pohang University of Science, Technology, Pohang, 790-784, South Korea (CSL, SHR); Department of Microbiology, Immunology,, Cancer Biology, University of Virginia, 1340 JPA, Charlottesville, Virginia 22908, USA (CSL); School of Interdisciplinary Bioscience, Bioengineering, Pohang University of Science, Technology, Pohang, 790-784, South Korea (SHR); Division of Integrative Biosciences, Biotechnology, Pohang University of Science, Technology, Pohang, 790-784, South Korea (SHR)

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Identity

Other alias
HGNC (Hugo) PLD2
LocusID (NCBI) 5338
Atlas_Id 43849
Location 17p13.2  [Link to chromosome band 17p13]
Location_base_pair Starts at 4807101 and ends at 4823432 bp from pter ( according to hg19-Feb_2009)  [Mapping PLD2.png]
Fusion genes
(updated 2016)
CKM (19q13.32) / PLD2 (17p13.2)PLD2 (17p13.2) / SYTL1 (1p36.11)RNF167 (17p13.2) / PLD2 (17p13.2)

DNA/RNA

 
  Figure 1. Organization of exons and introns in the human PLD2 (hPLD2) gene. Red rectangles (open and close) indicate exons and dark blue lines represent introns. Open red rectangles are non-coding exons and close red rectangles are coding exons. Blue rectangles indicate splicing variants in exon 23 of PLD2A and PLD2B. The diagram is not drawn to scale.
Description Location of the human PLD2 (hPLD2) gene is chromosome 17: 4710391 ~ 4726729 (forward strand) (Ensembl database: gene: PLD2, ENSG00000129219). hPLD2 has 25 exons and 24 coding exons.
Transcription Two transcripts of hPLD2 (hPLD2A and hPLD2B) code long-range proteins. As shown in figure 1, splicing variation in exon 23 gives rise to an 11 amino acid difference between the two. hPLD2A has a 3503 bp mRNA (933 amino acids) and hPLD2B has a 3391 bp mRNA (922 amino acids) (Ensembl database: PLD2A (transcript: ENST00000263088, protein: ENSP0000026308), PLD2B (transcript: ENST00000572940, protein: ENSP00000459571)).

Protein

 
  Figure 2. Organization of domains in hPLD2 protein. PX represents the phox homology (PX) domain, and PH indicates the pleckstrin homology (PH) domain. HKD represents the HKD domain (HxKxxxxD, x = any amino acid), which is the catalytic domain. The blue arrow indicates region that differ in hPLD2A and hPLD2B. The diagram is not drawn to scale.
Description Two products of hPLD2 can be generated by two transcripts (splicing variants). hPLD2A has 933 amino acids and hPLD2B has 922 amino acids. hPLD2B contains 11 amino acid deletions as compared with hPLD2A. These two products have evolutionally conserved domains. Like other members of the PLD superfamily, PLD2 also has a HKD domain (HxKxxxxDxxxxxxGSxN, x = any amino acid), which is essential for mediating PLD enzymatic activity (Frohman et al., 1999; Exton, 2002; Jenkins and Frohman, 2005). The phox homology (PX) domain and the pleckstrin homology (PH) domain are known to be involved in interactions with lipids and other proteins (Frohman et al., 1999; Sung et al., 1999; Exton, 2002). In particular, the PLD2-PX domain has been reported to interact with a variety of proteins, such as, dynamin, PLCγ, Cdk5, Grb2, and munc18 (Lee et al., 2009). In addition, the PLD2-PH domain is also involved in the interaction with Src and Rac2 (Ahn et al., 2003; Mahankali et al., 2011). The PLD2-PX domain can act as a guanine nucleotide exchange factor (GEF) for dynamin to enhance endocytosis and as a GEF for RhoA to induce LPA-mediated stress fiber formation (Lee et al., 2006; Jeon et al., 2011). Furthermore, the PLD2-PH domain can act as a GEF for Rac2 (Mahankali et al., 2011). Ckd5 has been reported to phosphorylate the PLD2-PX domain (Ser 134), and thus, mediate PLD2 activation and the secretion of insulin in a pancreatic β cell line (Lee et al., 2008a). Src also can interact with the PLD2-PH domain and phosphorylate PLD2 to mediate EGF-induced Src activation (Ahn et al., 2003). The Y169/Y179 residues of PLD2-PX domain are critically implicated in the interaction with Grb2 (Di Fulvio et al., 2006). This interaction is known to be important for the activation and intracellular localization of PLD2. In addition, the dissociation of munc-18 from the PLD2-PX domain is essential for EGF-induced PLD2 activation (Lee et al., 2004). The PLD2-PX domain interacts with the PLCγ-SH3 domain to mediate the EGF-induced activations of PLD2 and PLCγ (Jang et al., 2003). In addition to interacting with proteins, the PLD2-PH domain can interact with phosphoinositide 4,5-bisphosphate (PtdIns (4,5)P2), and this interaction is known to be important for the intracellular localization of PLD2 (Honda et al., 1999; Hodgkin et al., 2000; Sciorra et al., 2002). In the primary structures, the main difference between PLD1 and PLD2 is a loop region, that is, PLD1 has this region, whereas PLD2 does not (Colley et al., 1997; Hammond et al., 1997; Du et al., 2000; Peng and Frohman, 2012). It is considered that the loop region in PLD1 has autoinhibitory activity.
Expression PLD2 has been reported to be expressed in a variety type of tissues, such as, ovary, placenta, prostate, spinal cord, trachea, thymus, and thyroid. Specially, PLD2 mRNA has been detected in many different brain regions (Peng and Rhodes, 2000). During rat brain development, PLD2 mRNA levels are elevated and peak in the adult brain. In addition, PLD2 mRNA levels are transiently reduced during cerebral hypoxic-ischemic injury (Peng et al., 2006). Vessel occlusion-induced hypoxia in the hippocampus has been reported to increase PLD2 levels (Min do et al., 2007). Furthermore, the expression of PLD2 is known to be significantly elevated in many cancers, including breast, renal, and colon cancer (Zhao et al., 2000; Saito et al., 2007; Wood et al., 2007).
Localisation Most studies have found PLD2 is mainly localized in the plasma membrane (Du et al., 2004) and that PLD1 is primarily localized in specialized vesicles, such as, endoplasmic reticulum (ER), Golgi apparatus, secretory vesicles, endosomes, and lysosomes (Brown et al., 1998; Freyberg et al., 2001), and several reports indicate that PLD2 is also localized in cytoplasmic vesicles (Divecha et al., 2000). In addition, PLD2 can be translocated into the submembranous vesicles by serum and ruffling membranes by epidermal growth factor (EGF) (Colley et al., 1997; Honda et al., 1999). As mentioned above, the interaction between the PLD2-PH domain and PtdIns (4,5)P2 is important for the localization of PLD2. A PLD2-PH domain mutant incapable of interacting with PtdIns (4,5)P2 was not localized to the plasma membrane like wild-type PLD2, but localized to punctuate structures in cytoplasm (Sciorra et al., 2002).
Function PLD2 is a phosphatidylcholine (PC)-hydrolyzing enzyme and generates choline and phosphatidic acid (PA) (Jenkins and Frohman, 2005). PLD2 can be activated by multiple extracellular ligands and the major roles of PLD2 can be achieved by PA generation. PA is considered as a second messenger that mediates a variety of cellular functions such as, proliferation, cell growth, vesicle trafficking (endocytosis and exocytosis), and actin-cytoskeletal arrangement (Park et al., 2012). Furthermore, animal studies have shown that PLD2 can serve as a key mediator of in vivo pathophysiologic functions (Oliveira et al., 2010). Regardless PA generation, PLD2 protein can act as a GTPase-activating protein (GAP) for dynamin and a GEF for RhoA and Rac2 (Lee et al., 2006; Jeon et al., 2011; Mahankali et al., 2011). It is known that these functions of PLD2 and PA can be mediated by their binding partners (Jang et al., 2012). Currently, PLD2 and PA are known to have about 40 and 50 binding partners, respectively. Interacting partners include various classes of proteins (kinase, phosphatase, GTPase, structural protein, transporter, adapter, phospholipase, transcription factor), and phospholipids (PA, PtdIns5P, PtdIns(4,5)P2, and PtdIns(3,4,5)P3).

Proliferative signaling
Multiple extracellular mitogenic signals, such as, EGF, platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) can activate PLD2 to generate PA (Lee et al., 2009; Park et al., 2012). Specially, PLD2 is known to be implicated in EGF-mediated cell proliferation (Ahn et al., 2003). Furthermore, it has been well established that EGF signaling can be regulated via dynamic interactions between PLD2 (PA) and its binding partners (Lee et al., 2009). In addition, EGF can induce dissociation between PLD2 and munc-18 to activate PLD2 (Lee et al., 2004). Activated EGFR can recruit PLCγ to EGFR complex, and PLD2 can activate PLCγ which can generate IP3 and DAG for the activation of PKC (Jang et al., 2003). PLCγ can also serve as a GEF for dynamin (Choi et al., 2004). GTP-loaded dynamin and PKC can activate PLD2, which can act as a GAP for dynamin to potentiate EGFR endocytosis (Park et al., 2004; Lee et al., 2006). PA, generated by PLD activation, can recruit SOS to the plasma membrane. SOS acting as a GEF for Ras can activate the MAP kinase cascade (a key proliferative signaling pathway) and eventually induce cell proliferation and transformation (Zhao et al., 2007).

Cell growth signaling
Cells regulate cellular homeostasis by using extracellular nutrients and growth signals, and malfunctions in this process cause severe diseases, such as, cancer and diabetes. PLD2 acts as a key regulator of growth signaling mainly via the control of the mammalian target of rapamycin (mTOR), which is a key target for cancer treatment (Ha et al., 2006). Both PLD2 and PA can affect mTor signaling. PA can directly interact with the FRB domain of mTOR and activate mTOR (Toschi et al., 2009). Rapamycin (an anti-cancer drug) can inhibit mTOR activation by competing with PA for mTOR (Fang et al., 2001). In addition, PLD can bind Raptor, which complex strongly with mTOR, and interact with Rheb (an upstream GTPase of mTOR) in a GTP-dependent manner (Sun et al., 2008). Furthermore, these interactions are required for the activation of mTOR complex and the mediation of growth signaling.

Vesicle trafficking (endocytosis, and exocytosis)
PLD is known to be implicated in vesicle trafficking, such as, in intracellular vesicle trafficking, endocytosis, and exocytosis (Jones et al., 1999). In addition, PA generation by PLD has been reported to be involved in vesicle fusion by mediating inner membrane curvature (Jenkins and Frohman, 2005). Many reports have suggested that PLD1 is essentially involved in secretion and exocytosis (Vitale et al., 2001; Vitale et al., 2002), but recently, PLD2 was also found to be required for exocytosis. For example, Lee et al. reported that PLD2 is critically involved in insulin secretion by EGF in primary pancreatic islets and in a pancreatic beta cell line (Lee et al., 2008b). Also, PLD2 can induce angiotensin II-mediated aldosterone secretion from adrenal glomerulosa cells (Qin et al., 2010), and in addition to exocytosis, PLD2 is a well known essential mediator of receptor-mediated endocytosis and phagocytosis (Shen et al., 2001; Iyer et al., 2004). Furthermore, the overexpression of PLD2 wild-type can increase EGFR endocytosis, whereas the catalytic inactive PLD2 mutant does not (Shen et al., 2001). Moreover, mu-opioid receptor endocytosis and constitutive metabotropic glutamate receptor endocytosis can be affected by PLD2 activation (Koch et al., 2003; Bhattacharya et al., 2004). PLD2 activity can also regulate the phagocytosis of complement-opsonized zymosan in macrophages (Iyer et al., 2004). Many authors have suggested that PA generation by PLD2 activation is critically implicated in endocytosis and exocytosis. However, recently, it was reported that PLD2 itself, and not PLD2 activity, regulates endocytosis and phagocytosis (Lee et al., 2006; Mahankali et al., 2011). As we addressed above, PLD2 has GAP and GEF functions (PLD2-PX domain, which acts as a GAP for dynamin, and a PLD2-PH domain, which acts as a GEF for Rac2). Furthermore, the PLD2-GAP function for dynamin can accelerate EGF-mediated EGFR endocytosis and the PLD2-GEF function for Rac2 can increase phagocytosis in RAW264.7 macrophages.

Cytoskeletal rearrangement
Cells can undertake cytoskeletal changes by utilizing the dynamics of actin and tubulin (Berepiki et al., 2011; de Forges et al., 2012). These changes play a vital role in mediating a variety of cellular processes, such as, adhesion, spreading, migration, phagocytosis, and cytokinesis (Hynes, 2002). These processes are essential for pathophysiological functions, such as, organ morphogenesis and metastasis (Fletcher and Mullins, 2010). Several authors have suggested that PLD2 has a close relationship with cytoskeletal dynamics. For example, PLD2 can directly interact with kinases (PKC and PtdIns(4)P 5-Kinase) and small G proteins (Ral, Arf1, Arf4, and Arf6) that modulate cytoskeletal dynamics (Jang et al., 2012). Furthermore, cytoskeletal proteins, such as, actin and tubulin, can direct bind to PLD2 and inhibit its activity (Chae et al., 2005). Also, PA generation by PLD2 activation can activate PtdIns(4)P 5-Kinase to generate PtdIns(4,5)P2, which is involved in actin polymerization (Moritz et al., 1992). Also, integrin-mediated PA generation by PLD can recruit GTP-loaded Rac1 to the plasma membrane and be involved in activating Rac1 to mediate cell spreading and migration (Chae et al., 2008). Recently, in addition to PA generation by PLD2 activation, PLD2 (acting as a GEF) was found to be critically implicated in actin dynamics, for example, PLD2 can serve as a GEF for RhoA and Rac2 (Jeon et al., 2011; Mahankali et al., 2011). Furthermore, it has been reported that PLD2, acting as a GEF for RhoA, participates in LPA-mediated stress fiber formation and that PLD2, acting as a GEF for Rac2, is important for the mediations of migration and phagocytosis.

Homology We used PLD2A protein sequences (protein ID : ENSP00000263088) and aligned sequences with Multiple Sequence Alignment program at the website of the European Bioinformatics Institute (EMBL-EBI), and found the following:
- 55% sequence identity with PLD1a of Homo sapiens (protein ID: ENSP00000342793).
- 89% sequence identity with PLD2 of Mouse (protein ID: ENSMUSP00000018429).
- 85% sequence identity with PLD2 of Rat (protein ID: ENSRNOP00000053831).
- 57% sequence identity with PLD2 of Zebrafish (protein ID: ENSDARP00000122561).

Implicated in

Note
  
Entity Various cancers
Note Many reports have concluded that PLD2 is critically linked to the signals that mediate the processes involved tumorigenesis (transformation and tumor growth) and metastasis (Park et al., 2012). SOS, which activates the Ras-MAPK cascade, can be recruited to the plasma membrane by PLD2-derived PA generation, and eventually, MAPK signaling increases cell proliferation and transformation in NIH-3T3 cells (Zhao et al., 2007). As discussed above in cell growth signaling, PLD2 and PA can both directly affect mTor signaling, which is a main target of anti-cancer drugs, for example, rapamycin (a competitor of PA) is being used for tumor treatment. In addition, the expression level and activity of PLD2 have been reported to be elevated in several cancers, including colorectal cancer and renal cancer (Zhao et al., 2000; Saito et al., 2007), and to be associated with tumor size and survival (Saito et al., 2007). Furthermore, a PLD2 polymorphism detected in colorectal cancer was found to be closely linked to the prevalence of the disease (Wood et al., 2007). In the terms of metastasis, PLD has been implicated in the secretions of matrix metalloproteinase (MMP)-2 and MMP-9 in glioma and colorectal cancers, respectively (Kang et al., 2008; Park et al., 2009). Also, the overexpression of active PLD2 has been reported to increase the serum-induced cell invasion of EL4 lymphoma cells and to promote the metastasis of EL4 lymphoma cells into liver in syngeneic mice (Knoepp et al., 2008). Recently, PLD2 inhibitor was found to block the invasion of breast cancer cell lines, such as, the MDA-231, 4T1, and PMT cell lines (Scott et al., 2009). Therefore, the targeting of PLD2 and PA offers an important anti-tumor developmental strategy.
  
  
Entity Parkinson's disease
Note Parkinson's disease is a representative neurodegenerative disorder. α-Synuclein is the main component of Lewy bodies, the hallmark of Parkinson's disease, and elevated wild-type α-synuclein levels and polymorphisms of the α-synuclein gene are known to be closely linked to the severity and risk of developing Parkinson's disease (Parnetti et al., 2013). Furthermore, a physical interaction between PLD2 and α-synuclein reported in vivo can inhibit PLD2 activity (Jenco et al., 1998). Furthermore, PLD2 silencing by siRNA and the overexpression of α-synuclein have been reported to be associated with unusual behavioral deficits (Gorbatyuk et al., 2010). Although the implications of PLD2 in Parkinson's disease are not clear, further studies on the relations between PLD2 and α-Synuclein in Parkinson's disease are required.
  
  
Entity Alzheimer's disease
Note PLD is also implicated in Alzheimer's disease, another neurodegenerative disorder, which is characterized by amyloid β accumulation in brain tissues. PLD1 is known to interact with β-amyloid precursor protein and presenilins (PS1/PS2), which can mediate the proteolysis of β-amyloid precursor protein (Cai et al., 2006; Jin et al., 2007). Recently, an in vivo PLD2 KO mice study showed that PLD2 deficiency plays a role in protecting transgenic Alzheimer's disease mice from learning and memory deficits (Oliveira et al., 2010). However, regardless of changes in amyloid β and β-amyloid precursor protein, loss of PLD2 has been reported to mediate these protective effects via the recovery of synaptic protein (PSD95 and synaptophysin) levels. These observations suggest that PLD2 could be a potential therapeutic target in Alzheimer's disease.
  
  
Entity Hypertension
Note Hypertension is a major risk factor of cardiovascular diseases, such as, strokes and ischemic heart disease (Zhao et al., 2011). The etiology of hypertension is multi-factorial and includes genetic and environmental components. PLD elevation has been reported in vascular smooth muscle cells from spontaneously hypertensive rats (SHR; an animal model of hypertension) (Kondo et al., 1994; Freeman et al., 1995), and recently, genome-wide association studies (GWASs) showed that PLD2 is mutated (Arg172 to Cys) in patients with a hypertensive status (Hong et al., 2010). Although further studies on the interrelationship between PLD2 and hypertension are required, these GWASs demonstrated the biological relevance of PLD2 in the pathophysiology of hypertension.
  

To be noted

Acknowledgements: this work was supported by the grants (No. 2012R1A2A1A03010110 and NRF-M1AXA002-2012M3A6A4054249) of National Research Foundation funded by the Ministry of Education Science and Technology of Korea.

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J Biol Chem. 2003 Mar 14;278(11):9979-85. Epub 2003 Jan 7.
PMID 12519790
 
Enhanced phospholipase D activity in vascular smooth muscle cells derived from spontaneously hypertensive rats.
Kondo T, Inui H, Konishi F, Inagami T.
Clin Exp Hypertens. 1994 Jan;16(1):17-28.
PMID 8136772
 
The roles of phospholipase D in EGFR signaling.
Lee CS, Kim KL, Jang JH, Choi YS, Suh PG, Ryu SH.
Biochim Biophys Acta. 2009 Sep;1791(9):862-8. doi: 10.1016/j.bbalip.2009.04.007. Epub 2009 May 4. (REVIEW)
PMID 19410013
 
Cdk5 phosphorylates PLD2 to mediate EGF-dependent insulin secretion.
Lee HY, Jung H, Jang IH, Suh PG, Ryu SH.
Cell Signal. 2008a Oct;20(10):1787-94. doi: 10.1016/j.cellsig.2008.06.009. Epub 2008 Jun 25.
PMID 18625302
 
Munc-18-1 inhibits phospholipase D activity by direct interaction in an epidermal growth factor-reversible manner.
Lee HY, Park JB, Jang IH, Chae YC, Kim JH, Kim IS, Suh PG, Ryu SH.
J Biol Chem. 2004 Apr 16;279(16):16339-48. Epub 2004 Jan 26.
PMID 14744865
 
Epidermal growth factor increases insulin secretion and lowers blood glucose in diabetic mice.
Lee HY, Yea K, Kim J, Lee BD, Chae YC, Kim HS, Lee DW, Kim SH, Cho JH, Jin CJ, Koh DS, Park KS, Suh PG, Ryu SH.
J Cell Mol Med. 2008b Sep-Oct;12(5A):1593-604. Epub 2007 Dec 5.
PMID 18053093
 
Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the GTPase Rac2.
Mahankali M, Peng HJ, Henkels KM, Dinauer MC, Gomez-Cambronero J.
Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19617-22. doi: 10.1073/pnas.1114692108. Epub 2011 Nov 21.
PMID 22106281
 
Ischemic preconditioning upregulates expression of phospholipase D2 in the rat hippocampus.
Min do S, Choi JS, Kim HY, Shin MK, Kim MK, Lee MY.
Acta Neuropathol. 2007 Aug;114(2):157-62. Epub 2007 Mar 29.
PMID 17393174
 
Phosphatidic acid is a specific activator of phosphatidylinositol-4-phosphate kinase.
Moritz A, De Graan PN, Gispen WH, Wirtz KW.
J Biol Chem. 1992 Apr 15;267(11):7207-10.
PMID 1313792
 
Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits.
Oliveira TG, Chan RB, Tian H, Laredo M, Shui G, Staniszewski A, Zhang H, Wang L, Kim TW, Duff KE, Wenk MR, Arancio O, Di Paolo G.
J Neurosci. 2010 Dec 8;30(49):16419-28. doi: 10.1523/JNEUROSCI.3317-10.2010.
PMID 21147981
 
Phospholipase signalling networks in cancer.
Park JB, Lee CS, Jang JH, Ghim J, Kim YJ, You S, Hwang D, Suh PG, Ryu SH.
Nat Rev Cancer. 2012 Nov;12(11):782-92. doi: 10.1038/nrc3379. Epub 2012 Oct 18.
PMID 23076158
 
Overexpression of phospholipase D enhances matrix metalloproteinase-2 expression and glioma cell invasion via protein kinase C and protein kinase A/NF-kappaB/Sp1-mediated signaling pathways.
Park MH, Ahn BH, Hong YK, Min do S.
Carcinogenesis. 2009 Feb;30(2):356-65. doi: 10.1093/carcin/bgn287. Epub 2009 Jan 6.
PMID 19126647
 
Cerebrospinal fluid biomarkers in Parkinson disease.
Parnetti L, Castrioto A, Chiasserini D, Persichetti E, Tambasco N, El-Agnaf O, Calabresi P.
Nat Rev Neurol. 2013 Mar;9(3):131-40. doi: 10.1038/nrneurol.2013.10. Epub 2013 Feb 19.
PMID 23419373
 
Developmental expression of phospholipase D2 mRNA in rat brain.
Peng JF, Rhodes PG.
Int J Dev Neurosci. 2000 Oct;18(6):585-9.
PMID 10884603
 
Down-regulation of phospholipase D2 mRNA in neonatal rat brainstem and cerebellum after hypoxia-ischemia.
Peng JH, Feng Y, Rhodes PG.
Neurochem Res. 2006 Oct;31(10):1191-6. Epub 2006 Oct 6.
PMID 17024567
 
Mammalian phospholipase D physiological and pathological roles.
Peng X, Frohman MA.
Acta Physiol (Oxf). 2012 Feb;204(2):219-26. doi: 10.1111/j.1748-1716.2011.02298.x. Epub 2011 May 28. (REVIEW)
PMID 21447092
 
Phospholipase D2 mediates acute aldosterone secretion in response to angiotensin II in adrenal glomerulosa cells.
Qin H, Frohman MA, Bollag WB.
Endocrinology. 2010 May;151(5):2162-70. doi: 10.1210/en.2009-1159. Epub 2010 Mar 10.
PMID 20219982
 
Expression of phospholipase D2 in human colorectal carcinoma.
Saito M, Iwadate M, Higashimoto M, Ono K, Takebayashi Y, Takenoshita S.
Oncol Rep. 2007 Nov;18(5):1329-34.
PMID 17914593
 
Dual role for phosphoinositides in regulation of yeast and mammalian phospholipase D enzymes.
Sciorra VA, Rudge SA, Wang J, McLaughlin S, Engebrecht J, Morris AJ.
J Cell Biol. 2002 Dec 23;159(6):1039-49. Epub 2002 Dec 16.
PMID 12486109
 
Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, Brown HA.
Nat Chem Biol. 2009 Feb;5(2):108-17. doi: 10.1038/nchembio.140. Epub 2009 Jan 11.
PMID 19136975
 
Role for phospholipase D in receptor-mediated endocytosis.
Shen Y, Xu L, Foster DA.
Mol Cell Biol. 2001 Jan;21(2):595-602.
PMID 11134345
 
Phospholipase D1 is an effector of Rheb in the mTOR pathway.
Sun Y, Fang Y, Yoon MS, Zhang C, Roccio M, Zwartkruis FJ, Armstrong M, Brown HA, Chen J.
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8286-91. doi: 10.1073/pnas.0712268105. Epub 2008 Jun 11.
PMID 18550814
 
Structural analysis of human phospholipase D1.
Sung TC, Zhang Y, Morris AJ, Frohman MA.
J Biol Chem. 1999 Feb 5;274(6):3659-66.
PMID 9920915
 
Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin.
Toschi A, Lee E, Xu L, Garcia A, Gadir N, Foster DA.
Mol Cell Biol. 2009 Mar;29(6):1411-20. doi: 10.1128/MCB.00782-08. Epub 2008 Dec 29.
PMID 19114562
 
Phospholipase D1: a key factor for the exocytotic machinery in neuroendocrine cells.
Vitale N, Caumont AS, Chasserot-Golaz S, Du G, Wu S, Sciorra VA, Morris AJ, Frohman MA, Bader MF.
EMBO J. 2001 May 15;20(10):2424-34.
PMID 11350931
 
Regulated secretion in chromaffin cells: an essential role for ARF6-regulated phospholipase D in the late stages of exocytosis.
Vitale N, Chasserot-Golaz S, Bader MF.
Ann N Y Acad Sci. 2002 Oct;971:193-200.
PMID 12438119
 
The genomic landscapes of human breast and colorectal cancers.
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B.
Science. 2007 Nov 16;318(5853):1108-13. Epub 2007 Oct 11.
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Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos.
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Nat Cell Biol. 2007 Jun;9(6):706-12. Epub 2007 May 7.
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Nat Rev Cardiol. 2011 Jul 5;8(8):456-65. doi: 10.1038/nrcardio.2011.75. (REVIEW)
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Citation

This paper should be referenced as such :
Lee, CS ; Ryu, SH
PLD2 (phospholipase D2)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(9):633-639.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PLD2ID43849ch17p13.html


External links

Nomenclature
HGNC (Hugo)PLD2   9068
Cards
AtlasPLD2ID43849ch17p13
Entrez_Gene (NCBI)PLD2  5338  phospholipase D2
AliasesPLD1C
GeneCards (Weizmann)PLD2
Ensembl hg19 (Hinxton)ENSG00000129219 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000129219 [Gene_View]  chr17:4807101-4823432 [Contig_View]  PLD2 [Vega]
ICGC DataPortalENSG00000129219
TCGA cBioPortalPLD2
AceView (NCBI)PLD2
Genatlas (Paris)PLD2
WikiGenes5338
SOURCE (Princeton)PLD2
Genetics Home Reference (NIH)PLD2
Genomic and cartography
GoldenPath hg38 (UCSC)PLD2  -     chr17:4807101-4823432 +  17p13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PLD2  -     17p13.2   [Description]    (hg19-Feb_2009)
EnsemblPLD2 - 17p13.2 [CytoView hg19]  PLD2 - 17p13.2 [CytoView hg38]
Mapping of homologs : NCBIPLD2 [Mapview hg19]  PLD2 [Mapview hg38]
OMIM602384   
Gene and transcription
Genbank (Entrez)AB209374 AF033850 AF035483 AF038440 AF038441
RefSeq transcript (Entrez)NM_001243108 NM_002663
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PLD2
Cluster EST : UnigeneHs.104519 [ NCBI ]
CGAP (NCI)Hs.104519
Alternative Splicing GalleryENSG00000129219
Gene ExpressionPLD2 [ NCBI-GEO ]   PLD2 [ EBI - ARRAY_EXPRESS ]   PLD2 [ SEEK ]   PLD2 [ MEM ]
Gene Expression Viewer (FireBrowse)PLD2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5338
GTEX Portal (Tissue expression)PLD2
Protein : pattern, domain, 3D structure
UniProt/SwissProtO14939   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO14939  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO14939
Splice isoforms : SwissVarO14939
Catalytic activity : Enzyme3.1.4.4 [ Enzyme-Expasy ]   3.1.4.43.1.4.4 [ IntEnz-EBI ]   3.1.4.4 [ BRENDA ]   3.1.4.4 [ KEGG ]   
PhosPhoSitePlusO14939
Domaine pattern : Prosite (Expaxy)PLD (PS50035)    PX (PS50195)   
Domains : Interpro (EBI)PH_dom-like    PH_domain    Phox    PLD-like_dom    PLipase_D/transphosphatidylase    PLipase_D1/D2    PLipase_D_fam   
Domain families : Pfam (Sanger)PLDc (PF00614)    PLDc_2 (PF13091)    PX (PF00787)   
Domain families : Pfam (NCBI)pfam00614    pfam13091    pfam00787   
Domain families : Smart (EMBL)PH (SM00233)  PLDc (SM00155)  PX (SM00312)  
Conserved Domain (NCBI)PLD2
DMDM Disease mutations5338
Blocks (Seattle)PLD2
SuperfamilyO14939
Human Protein AtlasENSG00000129219
Peptide AtlasO14939
HPRD03857
IPIIPI00024727   IPI00216566   IPI00216567   
Protein Interaction databases
DIP (DOE-UCLA)O14939
IntAct (EBI)O14939
FunCoupENSG00000129219
BioGRIDPLD2
STRING (EMBL)PLD2
ZODIACPLD2
Ontologies - Pathways
QuickGOO14939
Ontology : AmiGOphospholipase D activity  protein binding  endoplasmic reticulum membrane  Golgi apparatus  plasma membrane  phosphatidic acid biosynthetic process  cytoskeleton organization  small GTPase mediated signal transduction  lipid catabolic process  phosphatidylinositol binding  synaptic vesicle recycling  Fc-gamma receptor signaling pathway involved in phagocytosis  inositol lipid-mediated signaling  cell motility  N-acylphosphatidylethanolamine-specific phospholipase D activity  presynapse  
Ontology : EGO-EBIphospholipase D activity  protein binding  endoplasmic reticulum membrane  Golgi apparatus  plasma membrane  phosphatidic acid biosynthetic process  cytoskeleton organization  small GTPase mediated signal transduction  lipid catabolic process  phosphatidylinositol binding  synaptic vesicle recycling  Fc-gamma receptor signaling pathway involved in phagocytosis  inositol lipid-mediated signaling  cell motility  N-acylphosphatidylethanolamine-specific phospholipase D activity  presynapse  
Pathways : BIOCARTAMetabolism of Anandamide, an Endogenous Cannabinoid [Genes]   
Pathways : KEGGGlycerophospholipid metabolism    Ether lipid metabolism    Ras signaling pathway    Endocytosis    Fc gamma R-mediated phagocytosis    Glutamatergic synapse    GnRH signaling pathway   
REACTOMEO14939 [protein]
REACTOME PathwaysR-HSA-2029485 [pathway]   
NDEx NetworkPLD2
Atlas of Cancer Signalling NetworkPLD2
Wikipedia pathwaysPLD2
Orthology - Evolution
OrthoDB5338
GeneTree (enSembl)ENSG00000129219
Phylogenetic Trees/Animal Genes : TreeFamPLD2
HOVERGENO14939
HOGENOMO14939
Homologs : HomoloGenePLD2
Homology/Alignments : Family Browser (UCSC)PLD2
Gene fusions - Rearrangements
Fusion : MitelmanRNF167/PLD2 [17p13.2/17p13.2]  [t(17;17)(p13;p13)]  
Fusion: TCGARNF167 17p13.2 PLD2 17p13.2 LUSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPLD2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PLD2
dbVarPLD2
ClinVarPLD2
1000_GenomesPLD2 
Exome Variant ServerPLD2
ExAC (Exome Aggregation Consortium)PLD2 (select the gene name)
Genetic variants : HAPMAP5338
Genomic Variants (DGV)PLD2 [DGVbeta]
DECIPHERPLD2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPLD2 
Mutations
ICGC Data PortalPLD2 
TCGA Data PortalPLD2 
Broad Tumor PortalPLD2
OASIS PortalPLD2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPLD2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPLD2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PLD2
DgiDB (Drug Gene Interaction Database)PLD2
DoCM (Curated mutations)PLD2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PLD2 (select a term)
intoGenPLD2
NCG5 (London)PLD2
Cancer3DPLD2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602384   
Orphanet
MedgenPLD2
Genetic Testing Registry PLD2
NextProtO14939 [Medical]
TSGene5338
GENETestsPLD2
Target ValidationPLD2
Huge Navigator PLD2 [HugePedia]
snp3D : Map Gene to Disease5338
BioCentury BCIQPLD2
ClinGenPLD2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5338
Chemical/Pharm GKB GenePA33397
Clinical trialPLD2
Miscellaneous
canSAR (ICR)PLD2 (select the gene name)
Probes
Litterature
PubMed138 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePLD2
EVEXPLD2
GoPubMedPLD2
iHOPPLD2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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