PLD1 (phospholipase D1, phosphatidylcholine-specific)

2010-10-01   Chang 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




Atlas Image
Exons are represented by red rectangles and introns by lines. The picture is not represented by exact scale.


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)).


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)).


Atlas Image
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.


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.


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).


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).


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 PtdIns(4)P 5-Kinase (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).


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 name
Various cancers
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 name
Alzheimers disease
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.


Pubmed IDLast YearTitleAuthors
96633931998Phospholipase D1 localises to secretory granules and lysosomes and is plasma-membrane translocated on cellular stimulation.Brown FD et al
156683892005Requirement of phospholipase D1 activity in H-RasV12-induced transformation.Buchanan FG et al
164493862006Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation.Cai D et al
164493852006Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons.Cai D et al
169167822006Phospholipid signalling through phospholipase D and phosphatidic acid.Cazzolli R et al
184804132008Phospholipase D activity regulates integrin-mediated cell spreading and migration by inducing GTP-Rac translocation to the plasma membrane.Chae YC et al
157745482005Phospholipase D (PLD) gene expression in human neutrophils and HL-60 differentiation.Di Fulvio M et al
128762782003Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs.Du G et al
200515932010Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1.Elvers M et al
117293232001Phosphatidic acid-mediated mitogenic activation of mTOR signaling.Fang Y et al
145173412003Phospholipase D in cell proliferation and cancer.Foster DA et al
167781312006Selective activation of nuclear phospholipase D-1 by g protein-coupled receptor agonists in vascular smooth muscle cells.Gayral S et al
85303461995Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family.Hammond SM et al
124298402002Localization of phospholipase D1 to caveolin-enriched membrane via palmitoylation: implications for epidermal growth factor signaling.Han JM et al
106603032000Phospholipase D regulation and localisation is dependent upon a phosphatidylinositol 4,5-biphosphate-specific PH domain.Hodgkin MN et al
105896801999Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation.Honda A et al
157721572005Insulin-stimulated plasma membrane fusion of Glut4 glucose transporter-containing vesicles is regulated by phospholipase D1.Huang P et al
150874632004Phospholipase D1 regulates secretagogue-stimulated insulin release in pancreatic beta-cells.Hughes WE et al
113896802001Endosomal localization of phospholipase D 1a and 1b is defined by the C-termini of the proteins, and is independent of activity.Hughes WE et al
151991262004Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53.Hui L et al
117524682001A role for phospholipase D1 in neurotransmitter release.Humeau Y et al
126465822003The direct interaction of phospholipase C-gamma 1 with phospholipase D2 is important for epidermal growth factor signaling.Jang IH et al
161438292005Phospholipase D: a lipid centric review.Jenkins GM et al
167977882007Phospholipase D1 is associated with amyloid precursor protein in Alzheimer's disease.Jin JK et al
169732782006Phospholipase D1 is up-regulated in the mitochondrial fraction from the brains of Alzheimer's disease patients.Jin JK et al
102231831999Sustained phospholipase D activation is associated with keratinocyte differentiation.Jung EM et al
193418132009Phospholipase D signalling and its involvement in neurite outgrowth.Kanaho Y et al
180840052008Phorbol ester up-regulates phospholipase D1 but not phospholipase D2 expression through a PKC/Ras/ERK/NFkappaB-dependent pathway and enhances matrix metalloproteinase-9 secretion in colon cancer cells.Kang DW et al
104411281999Phosphorylation and activation of phospholipase D1 by protein kinase C in vivo: determination of multiple phosphorylation sites.Kim Y et al
185231402008Effects of active and inactive phospholipase D2 on signal transduction, adhesion, migration, invasion, and metastasis in EL4 lymphoma cells.Knoepp SM et al
194100132009The roles of phospholipase D in EGFR signaling.Lee CS et al
147448652004Munc-18-1 inhibits phospholipase D activity by direct interaction in an epidermal growth factor-reversible manner.Lee HY et al
197632552009Determination of EGFR endocytosis kinetic by auto-regulatory association of PLD1 with mu2.Lee JS et al
104253961999Expression of phospholipase D isoforms in mammalian cells.Meier KE et al
110909712000Overexpression of phospholipase D1 in human breast cancer tissues.Noh DY et al
79169021994Novel ketoepoxides block phospholipase D activation and tumor cell invasion.Pai JK et al
191266472009Overexpression 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 et al
158435152005An essential role for phospholipase D in the activation of protein kinase C and degranulation in mast cells.Peng Z et al
194229322009Inter-regulatory dynamics of phospholipase D and the actin cytoskeleton.Rudge SA et al
179145932007Expression of phospholipase D2 in human colorectal carcinoma.Saito M et al
154753612004Mechanism of membrane binding of the phospholipase D1 PX domain.Stahelin RV et al
199030732009Targeting phospholipase D with small-molecule inhibitors as a potential therapeutic approach for cancer metastasis.Su W et al
185508142008Phospholipase D1 is an effector of Rheb in the mTOR pathway.Sun Y et al
99209151999Structural analysis of human phospholipase D1.Sung TC et al
99290051999Colocalization of phospholipase D1 and GTP-binding-defective mutant of ADP-ribosylation factor 6 to endosomes and lysosomes.Toda K et al
93819751997Role and regulation of phospholipase D activity in normal and cancer cells.Wakelam MJ et al
126015292003Association of a polymorphism of the phospholipase D2 gene with the prevalence of colorectal cancer.Yamada Y et al
181981862008PLD regulates myoblast differentiation through the mTOR-IGF2 pathway.Yoon MS et al
174861152007Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos.Zhao C et al

Other Information

Locus ID:

NCBI: 5337
MIM: 602382
HGNC: 9067
Ensembl: ENSG00000075651


dbSNP: 5337
ClinVar: 5337
TCGA: ENSG00000075651


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Glycerophospholipid metabolismKEGGko00564
Ether lipid metabolismKEGGko00565
GnRH signaling pathwayKEGGko04912
Pancreatic cancerKEGGko05212
Glycerophospholipid metabolismKEGGhsa00564
Ether lipid metabolismKEGGhsa00565
GnRH signaling pathwayKEGGhsa04912
Pathways in cancerKEGGhsa05200
Pancreatic cancerKEGGhsa05212
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Metabolic pathwaysKEGGhsa01100
Glutamatergic synapseKEGGko04724
Glutamatergic synapseKEGGhsa04724
Ras signaling pathwayKEGGhsa04014
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Choline metabolism in cancerKEGGhsa05231
Choline metabolism in cancerKEGGko05231
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
Role of phospholipids in phagocytosisREACTOMER-HSA-2029485
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Phospholipid metabolismREACTOMER-HSA-1483257
Glycerophospholipid biosynthesisREACTOMER-HSA-1483206
Synthesis of PAREACTOMER-HSA-1483166
Synthesis of PGREACTOMER-HSA-1483148
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
Neutrophil degranulationREACTOMER-HSA-6798695

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
185508142008Phospholipase D1 is an effector of Rheb in the mTOR pathway.88
128134672003Phospholipase D confers rapamycin resistance in human breast cancer cells.77
220241662011Class III PI-3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway.67
231318462012Key roles for the lipid signaling enzyme phospholipase d1 in the tumor microenvironment during tumor angiogenesis and metastasis.57
166224172006The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis.54
164493862006Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation.49
168736752006Phagocyte cell migration is mediated by phospholipases PLD1 and PLD2.45
184804132008Phospholipase D activity regulates integrin-mediated cell spreading and migration by inducing GTP-Rac translocation to the plasma membrane.44
118213922002alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells.41
193667062009Phospholipase D-mediated activation of IQGAP1 through Rac1 regulates hyperoxia-induced p47phox translocation and reactive oxygen species generation in lung endothelial cells.35


Chang Sup Lee ; Sung Ho Ryu

PLD1 (phospholipase D1, phosphatidylcholine-specific)

Atlas Genet Cytogenet Oncol Haematol. 2010-10-01

Online version: