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PLD1 (phospholipase D1, phosphatidylcholine-specific)

Written2010-10Chang Sup Lee, Sung Ho Ryu
Department of Life Science, Division of Molecular, Life Sciences, Division of Integrative Biosciences, Biotechnology, WCU program, Pohang University of Science, Technology, Pohang, 790-784, South Korea

(Note : for Links provided by Atlas : click)


HGNC (Hugo) PLD1
HGNC Alias namecholine phosphatase 1
HGNC Previous namephospholipase D1, phosphatidylcholine-specific
LocusID (NCBI) 5337
Atlas_Id 43716
Location 3q26.31  [Link to chromosome band 3q26]
Location_base_pair Starts at 171600404 and ends at 171810483 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PLD1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
MGAT4C (12q21.31)::PLD1 (3q26.31)OSBPL2 (20q13.33)::PLD1 (3q26.31)PLD1 (3q26.31)::AGBL1 (15q25.3)
PLD1 (3q26.31)::RPS19 (19q13.2)TFDP2 (3q23)::PLD1 (3q26.31)


  Exons are represented by red rectangles and introns by lines. The picture is not represented by exact scale.
Description The PLD1 gene is composed of 27 exons (PLD1a) or 26 exons (PLD1b) and introns spanning 209658 bp. It starts at 171318616 and ends at 171528273 (NCBI database: entrez gene: PLD1 phospholipase D1, phosphatidylcholine-specific (Homo sapiens)).
Transcription PLD1 DNA has two transcripts by alternative splicing. (PLD1a: 27 exons, 5607 bp mRNA, 1074 amino acids, PLD1b: 26 exons, 5493 bp mRNA, 1036 amino acids) (NCBI database: NCBI Reference Sequence: NM_002662.3 (PLD1a), NM_001130081.1 (PLD1b)).


  PX: Phox homology (PX) domain; PH: Pleckstrin homology (PH) domain; Loop: Loop region; I, II, III, IV: conserved regions I, II, III, and IV; The red arrow indicates the difference between PLD1a and PLD1b.
Description PLD1 (MW: about 120 kDa) contains the several conserved domains/regions (Hammond et al., 1995). PLD superfamily has a well-conserved HKD motif (HXK[X]4D[X]6GSXN), which is in conserved regions II and IV that mediate PLD enzymatic activity. In addition, the PX and PH domains are known to be implicated in interactions with other proteins and phosphoinositide 4,5-bisphosphate (PtdIns (4,5)P2), respectively (Sung et al., 1999). Recently, the PX and PH domains of PLD have been reported to be the core binding regions of PLD and to mediate its functions.
For example, dynamin and μ2 showed the effects on EGFR-mediated endocytosis via R128/R197 of the PLD1-PX domain and R304 of the PLD1-PH domain, respectively (Lee et al., 2006; Lee et al., 2009b). Also, PLCgamma and munc18 can interact with the P161/P164 of the PLD1-PX domain and the C-terminal region (184~212 residues) of the PLD1-PX domain, respectively (Jang et al., 2003; Lee et al., 2004). These interactions occur in an EGF-dependent manner and contribute to the regulation of PLD activity. Furthermore, PKCalpha can phosphorylate the T147 of the PLD1-PX domain to increase PLD activity (Kim et al., 1999). In addition, to protein interactions, these domains can interact with phospholipids. Recently, it has been reported that phosphoinositide 3,4,5-bisphosphate (PtdIns (3,4,5)P3 interacts with the R179 of the PLD1-PX domain and can stimulate PLD activity (Lee et al., 2005).
Phosphatidic acid-(PA) can also bind to PLD via a secondary lipid-binding pocket residue (R158) in the PLD1-PX domain (Stahelin et al., 2004). In addition, PLD1-PH domain also interacts with phosphoinositide 4,5-bisphosphate (PtdIns (4,5)P2 (Hodgkin et al., 2000). It has been reported that this interaction can regulate PLD activity and localization.
Expression PLD1 is ubiquitously expressed in a variety of tissues including brain, lung, heart, liver, adipose tissue, and spleen (Meier et al., 1999). The expression level of PLD1 is elevated in several cancer cells (Noh et al., 2000; Buchanan et al., 2005).
Localisation It is believed that PLD1 is primarily localized in perinuclear regions, such as, endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles (Jenkins et al., 2005). Several reports have suggested that PLD1 is also localized in endosomes (early, late, and recycling) and lysomes (Toda et al., 1999; Hughes et al., 2001; Du et al., 2003). Furthermore, PLD1 can translocate to the plasma membrane in a signal-dependent manner (Brown et al., 1998), and can be localized in specialized region (caveolae) of the plasma membrane. The C240/C241 residues of PLD1 are palmitoylated to localize at caveolae, and this localization is important for mediating EGF signaling (Han et al., 2002). Recently, it was reported that PLD1 also has nuclear roles (Gayral et al., 2006).
Function PLD1 is a phospholipid-hydrolyzing enzyme that can catalyze phosphatidylcholine (PC) to generate phosphatidic acid (PA) and choline. PA can function as a second messenger and can be converted to other biomolecules, such as, LPA and DAG (Jenkins et al., 2005). PA can interact with a variety of molecules to recruit it to the membrane. For example, PA binds to mTOR-FRB domain and regulates its cell growth signaling activity (Fang et al., 2001), and can interact with (Honda et al., 1999); this latter interaction can modulate the generation of PtdIns(4,5)P2. Recently, it was been reported that PA can translocate SOS to the plasma membrane to mediate EGF signaling (Zhao et al., 2007). PLD can mediate many cellular phenomena, such as, proliferation, vesicle trafficking, cytoskeleton reorganization, and differentiation, and recently, Elvers et al. after a study on PLD1 knockout mice, reported that PLD1 can modulate thrombus formation via platelet aggregation (Elvers et al., 2010).

PLD can be activated by a variety of mitogenic signals - epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), insulin, growth hormones, lysophosphatidic acid (LPA), and spingosine 1-phosphate - all of which can directly bind with G-protein coupled receptors (GPCR) and receptor-tyrosine kinases (RTK). PLD activation via mitogenic signals can induce cell proliferation, cell survival, the suppression of cell cycle arrest, and the prevention of apoptosis (Foster et al., 2003; Lee et al., 2009a; Su et al., 2009). Furthermore, elevated PLD activity has been shown to transform cells (Buchanan et al., 2005).

Vesicle trafficking
It has been reported that PLD is critically involved in vesicle formation and trafficking, such as, in endocytosis, exocytosis, and vesicle formation from the trans-Golgi network (Cazzolli et al., 2006). PLD-derived PA generation can recruit downstream molecules (PtdIns(4)P 5-Kinase) that are involved in vesicle fusion and mediate the inner membrane curvature (Jenkins et al., 2005). Many reports have suggested that PA generation by PLD can contribute to exocytosis (immune cell degranulation, neurotransmitter secretion, and EGF secretion) in various cell lines, such as, mast cells, adipocytes, and neuroendocrine cells. Furthermore, endocytosis (receptor mediated endocytosis and phagocytosis) also depends on PA generation by PLD (Humeau et al., 2001; Hughes et al., 2004; Huang et al., 2005; Peng et al., 2005). Recently, we have been suggested that PLD protein can increase the GTPase activity of dynamin, which is important for endocytosis, and that PLD itself, and not PA, can increase EGFR endocytosis (Lee et al., 2006).

Cytoskeletal reorganization
PA generation by PLD activation has been shown to be a key regulator of cytoskeletal dynamics to induce cell adhesion, spreading, and migration. PLD can be activated by kinases (PKC and PtdIns(4)P 5-Kinase) and small G proteins (Rho, Rac, cdc42, Arf, and Ral) that mediate signaling essentially required for cytoskeletal reorganization (Rudge et al., 2009). Moreover, PLD-derived PA can translocate GTP-Rac to the plasma membrane and induce integrin-mediated cell spreading (Chae et al., 2008).

PLD appears to be involved in the differentiation of various cells. Prolonged PA generation by PLD activation is correlated with the differentiation of keratinocytes (Jung et al., 1999), and the PLD isozyme expression levels are increased during granulocytic differentiation (Di Fulvio et al., 2005). PLD is well known to have an essential role during neuronal cell differentiation (Kanaho et al., 2009). Recently, Yoon et al reported that PLD can induce myoblast differentiation via the secretion of IGF2 in an autocrine manner (Yoon et al., 2008).

Homology A blast search produced the following results:
85% sequence identity in Mus musculus.
87% sequence identity in Rattus norvegicus.
47% sequence identity in C. elegans.
56% sequence identity with PLD2 of Homo sapiens.

Implicated in

Entity Various cancers
Note Several tumor cells (breast cancer, colon cancer) show elevated PLD1 expression and activity. For example, the expression and activity of PLD1 are upregulated in breast cancer tissue. Also, the expression of PLD1/PLD2 is upregulated in colon cancer (Noh et al., 2000; Buchanan et al., 2005; Saito et al., 2007). Furthermore, a polymorphism of PLD2 was shown to be associated with the prevalence of colorectal cancer (Yamada et al., 2003). Increased PLD1 activity/expression can transform rat fibroblasts. It has been shown that the mTor pathway can contribute to the growth and survival of cancer cells. Moreover, elevated PLD1 levels can increase the phosphorylation of S-6 kinase, which is a downstream molecule in mTor signaling (Hui et al., 2004).
Recently, PLD1 was shown to activate Rheb, which is upstream of the GTPase of mTor (Sun et al., 2008). Furthermore, PLD has also been implicated in the invasion of tumor cells and in the secretion of matrix metalloproteinases (MMP) (Pai et al., 1994; Wakelam et al., 1997; Knoepp et al., 2008; Park et al., 2009). In particular, the upregulation of PLD1 by PMA was shown to increase the secretion of MMP9 in colon cancer cells (Kang et al., 2008).
Entity Alzheimer's disease
Note The expression and activity of PLD1 is increased in the AD (Alzheimer Disease) brain.
Beta-Amyloid precursor protein (beta-APP), which is involved in the pathogenesis of AD, has been shown to interact with PLD1-PH domain and elevated APP levels increased PLD activity in astroglioma cells (Jin et al., 2006; Jin et al., 2007). Also, the presenilins (PS1/PS2), which can mediate the proteolysis of beta-amyloid precursor protein, have been shown to interact with PLD1. Furthermore, the generation of beta-amyloid from beta-APP containing vesicles was found to be decreased by the overexpression of PLD1, which also promoted the budding out of beta-APP containing vesicles (Cai et al., 2006a; Cai et al., 2006b). Although evidence exists that PLD1 is associated with AD, the pathophysiological relationship between PLD1 and AD needs further study.

To be noted

Acknowledgements: This work was supported in part by the FPR08B1-300 of the 21C Frontier functional proteomics project and by the World class university program through the National research foundation of Korea funded by the Ministry of education, science and technology (R31-2008-000-10105-0).


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This paper should be referenced as such :
Lee, CS ; Ryu, SH
PLD1 (phospholipase D1, phosphatidylcholine-specific)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(6):511-515.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)PLD1   9067
Entrez_Gene (NCBI)PLD1    phospholipase D1
GeneCards (Weizmann)PLD1
Ensembl hg19 (Hinxton)ENSG00000075651 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000075651 [Gene_View]  ENSG00000075651 [Sequence]  chr3:171600404-171810483 [Contig_View]  PLD1 [Vega]
ICGC DataPortalENSG00000075651
TCGA cBioPortalPLD1
AceView (NCBI)PLD1
Genatlas (Paris)PLD1
SOURCE (Princeton)PLD1
Genetics Home Reference (NIH)PLD1
Genomic and cartography
GoldenPath hg38 (UCSC)PLD1  -     chr3:171600404-171810483 -  3q26.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PLD1  -     3q26.31   [Description]    (hg19-Feb_2009)
GoldenPathPLD1 - 3q26.31 [CytoView hg19]  PLD1 - 3q26.31 [CytoView hg38]
Genome Data Viewer NCBIPLD1 [Mapview hg19]  
OMIM212093   602382   
Gene and transcription
Genbank (Entrez)AB209907 AJ276230 AK026225 AK091897 BC068976
RefSeq transcript (Entrez)NM_001130081 NM_002662
Consensus coding sequences : CCDS (NCBI)PLD1
Gene ExpressionPLD1 [ NCBI-GEO ]   PLD1 [ EBI - ARRAY_EXPRESS ]   PLD1 [ SEEK ]   PLD1 [ MEM ]
Gene Expression Viewer (FireBrowse)PLD1 [ Firebrowse - Broad ]
GenevisibleExpression of PLD1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5337
GTEX Portal (Tissue expression)PLD1
Human Protein AtlasENSG00000075651-PLD1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13393   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ13393  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13393
Domaine pattern : Prosite (Expaxy)PLD (PS50035)    PX (PS50195)   
Domains : Interpro (EBI)PH-like_dom_sf    PH_domain    PLD-like_dom    PLipase_D/transphosphatidylase    PLipase_D_euk    PLipase_D_fam    PX_dom    PX_dom_sf   
Domain families : Pfam (Sanger)PH (PF00169)    PLDc (PF00614)    PLDc_2 (PF13091)    PX (PF00787)   
Domain families : Pfam (NCBI)pfam00169    pfam00614    pfam13091    pfam00787   
Domain families : Smart (EMBL)PH (SM00233)  PLDc (SM00155)  PX (SM00312)  
Conserved Domain (NCBI)PLD1
PDB Europe6U8Z   
PDB (PDBSum)6U8Z   
PDB (IMB)6U8Z   
Structural Biology KnowledgeBase6U8Z   
SCOP (Structural Classification of Proteins)6U8Z   
CATH (Classification of proteins structures)6U8Z   
AlphaFold pdb e-kbQ13393   
Human Protein Atlas [tissue]ENSG00000075651-PLD1 [tissue]
Protein Interaction databases
IntAct (EBI)Q13393
Ontologies - Pathways
Ontology : AmiGOGolgi membrane  phospholipase D activity  protein binding  lysosomal membrane  endosome  endoplasmic reticulum membrane  Golgi apparatus  plasma membrane  phosphatidic acid biosynthetic process  chemotaxis  small GTPase mediated signal transduction  Ras protein signal transduction  membrane  lipid catabolic process  apical plasma membrane  endocytic vesicle  late endosome membrane  regulation of microvillus assembly  regulation of microvillus assembly  phosphatidylinositol binding  specific granule membrane  neutrophil degranulation  positive regulation of translation  inositol lipid-mediated signaling  perinuclear region of cytoplasm  cell motility  N-acylphosphatidylethanolamine-specific phospholipase D activity  tertiary granule membrane  regulation of synaptic vesicle cycle  regulation of synaptic vesicle cycle  cholinergic synapse  cholinergic synapse  
Ontology : EGO-EBIGolgi membrane  phospholipase D activity  protein binding  lysosomal membrane  endosome  endoplasmic reticulum membrane  Golgi apparatus  plasma membrane  phosphatidic acid biosynthetic process  chemotaxis  small GTPase mediated signal transduction  Ras protein signal transduction  membrane  lipid catabolic process  apical plasma membrane  endocytic vesicle  late endosome membrane  regulation of microvillus assembly  regulation of microvillus assembly  phosphatidylinositol binding  specific granule membrane  neutrophil degranulation  positive regulation of translation  inositol lipid-mediated signaling  perinuclear region of cytoplasm  cell motility  N-acylphosphatidylethanolamine-specific phospholipase D activity  tertiary granule membrane  regulation of synaptic vesicle cycle  regulation of synaptic vesicle cycle  cholinergic synapse  cholinergic synapse  
Pathways : BIOCARTARas Signaling Pathway [Genes]    Rac 1 cell motility signaling pathway [Genes]    Metabolism 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    Pathways in cancer    Pancreatic cancer   
REACTOMEQ13393 [protein]
REACTOME PathwaysR-HSA-6798695 [pathway]   
NDEx NetworkPLD1
Atlas of Cancer Signalling NetworkPLD1
Wikipedia pathwaysPLD1
Orthology - Evolution
GeneTree (enSembl)ENSG00000075651
Phylogenetic Trees/Animal Genes : TreeFamPLD1
Homologs : HomoloGenePLD1
Homology/Alignments : Family Browser (UCSC)PLD1
Gene fusions - Rearrangements
Fusion : MitelmanMGAT4C::PLD1 [12q21.31/3q26.31]  
Fusion : MitelmanOSBPL2::PLD1 [20q13.33/3q26.31]  
Fusion : MitelmanPLD1::AGBL1 [3q26.31/15q25.3]  
Fusion : MitelmanTFDP2::PLD1 [3q23/3q26.31]  
Fusion : FusionGDB3.1.4.4   
Fusion : QuiverPLD1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPLD1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PLD1
Exome Variant ServerPLD1
GNOMAD BrowserENSG00000075651
Varsome BrowserPLD1
ACMGPLD1 variants
Genomic Variants (DGV)PLD1 [DGVbeta]
DECIPHERPLD1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPLD1 
ICGC Data PortalPLD1 
TCGA Data PortalPLD1 
Broad Tumor PortalPLD1
OASIS PortalPLD1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPLD1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPLD1
Mutations and Diseases : HGMDPLD1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)PLD1
DoCM (Curated mutations)PLD1
CIViC (Clinical Interpretations of Variants in Cancer)PLD1
NCG (London)PLD1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM212093    602382   
Genetic Testing Registry PLD1
NextProtQ13393 [Medical]
Target ValidationPLD1
Huge Navigator PLD1 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDPLD1
Pharm GKB GenePA164742228
Clinical trialPLD1
DataMed IndexPLD1
PubMed173 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:25:25 CEST 2021

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