Affinage

PLD1

Phospholipase D1 · UniProt Q13393

Length
1074 aa
Mass
124.2 kDa
Annotated
2026-06-10
72 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLD1 is a phosphatidylcholine-hydrolyzing phospholipase whose generation of the signaling lipid phosphatidic acid (PA) at intracellular membranes serves as a regulatory hub for vesicle trafficking, organelle biogenesis, growth signaling, and cytoskeletal control (PMID:32198492, PMID:14653992). Its catalytic domain folds into a funnel-shaped hydrophobic cavity feeding the active site, with a membrane-interface polybasic pocket that binds PIP2 (essential for activity), a C-terminal contribution to the catalytic pocket, a phosphohistidine intermediate, and a defined RhoA-binding surface (PMID:32198492). Enzyme activity and membrane targeting are tuned by multiple inputs: palmitoylation on Cys240/241 strengthens membrane association (PMID:11121416), Ca2+/calmodulin and PKCalpha stimulate activity (PMID:10838164), RSK2 directly phosphorylates Thr-147 in the N-terminal PX domain to activate the enzyme (PMID:18550821), and Arf-family GTPases including Arf1, ARL11, and ARL14 promote activity and membrane recruitment (PMID:16054594, PMID:35844135). Through PA production PLD1 acts upstream of the mTOR-S6K1 axis to regulate cell size and (via DEPTOR displacement and IRS-1 phosphorylation) insulin signaling and adipogenesis (PMID:14653992, PMID:27872488). PLD1-derived PA drives lipid-droplet biogenesis through an ERK2-dynein pathway and, upon RalA-dependent lysosomal recruitment during nutrient depletion, recruits perilipin 3 to growing droplets (PMID:16723731, PMID:34320341), supports COPII-dependent ER-to-Golgi transport (PMID:28648601), couples PA production to AP2/mu2 recruitment for EGFR endocytosis (PMID:19763255), and provides PA at ATG16L1-positive precursor membranes during autophagy under HS1BP3 control (PMID:28318354). In neurons, RSK2-PLD1 signaling promotes neurite outgrowth via VAMP-7 vesicle fusion and BDNF-driven ERK/CREB and mTOR signaling, while PA acting downstream of RhoA restricts dendritic branching (PMID:24336713, PMID:26437780, PMID:22674271). Loss-of-function PLD1 mutations that reduce catalytic activity cause congenital right-sided cardiac valve defects, linked to impaired endothelial-mesenchymal transition during valvulogenesis (PMID:33645542).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established the upstream regulatory inputs to PLD1 activity, defining how lipid modification and second messengers control the enzyme at membranes.

    Evidence Cysteine mutagenesis with palmitoylation labeling and membrane fractionation, plus Sf9 co-expression with PKCalpha and Ca2+/calmodulin reconstitution assays

    PMID:10838164 PMID:11121416

    Open questions at the time
    • Whether palmitoylation and phosphorylation act on the same membrane pool was not resolved
    • PKCalpha activation characterized in an overexpression insect-cell system
  2. 2003 High

    Placed PLD1 upstream of mTOR-S6K1, showing PA as the link between Cdc42 and cell-size control.

    Evidence RNAi knockdown, dominant-negative catalytically inactive PLD1, S6K1 epistasis, and exogenous PA rescue of a PLD1-inactive Cdc42 mutant

    PMID:14653992

    Open questions at the time
    • Direct molecular target of PA within the mTOR complex not defined here
    • Did not address tissue specificity of the Cdc42-PLD1-mTOR axis
  3. 2006 High

    Defined a PLD1-specific (not PLD2) role in cytosolic lipid droplet formation and ordered the pathway PLD1 to ERK2 to dynein.

    Evidence siRNA, overexpression, anti-dynein microinjection, pharmacological ERK2 inhibition, and Arf1-dependent localization with Brefeldin A in NIH3T3 cells

    PMID:16054594 PMID:16723731

    Open questions at the time
    • How PA links to dynein phosphorylation mechanistically not established
    • Direct vs indirect Arf1 effect on droplet-localized PLD1 not separated
  4. 2008 High

    Identified the direct activating phosphorylation of PLD1 at Thr-147 by RSK2, connecting calcium-stimulated kinase signaling to regulated exocytosis.

    Evidence Co-IP, phosphomimetic T147 mutant rescue of secretion in RSK2-depleted chromaffin cells, and PLD activity assays

    PMID:18550821

    Open questions at the time
    • Structural basis of Thr-147 phosphorylation effect on the PX domain not shown
    • Other RSK2 substrates contributing to secretion not excluded
  5. 2009 Medium

    Showed PLD1 uses its own PA product to recruit endocytic machinery, providing a feedforward mechanism for receptor internalization.

    Evidence Co-IP of PLD1 with AP2 subunit mu2, PA-binding requirement by mutagenesis, and EGFR endocytosis kinetics

    PMID:19763255

    Open questions at the time
    • Single Co-IP without reciprocal structural mapping of the mu2 interface
    • Generality across other cargo receptors not tested
  6. 2013 High

    Extended the RSK2-PLD1 axis to neuronal membrane expansion, linking it to VAMP-7-dependent vesicle fusion driving neurite outgrowth.

    Evidence Phosphomimetic PLD1 rescue in RSK2-silenced PC12 cells, TIRF imaging of VAMP-7 fusion, and Pld1 knockout mouse neurons

    PMID:24336713

    Open questions at the time
    • Direct PA-VAMP7 fusion machinery link not mechanistically dissected
  7. 2016 Medium

    Connected PLD1-derived PA to mTORC1 regulation via DEPTOR displacement, explaining suppression of insulin signaling and adipogenesis.

    Evidence PLD1 inhibitor, siRNA, PA treatment, mTORC1 pull-down showing DEPTOR displacement, and phospho-IRS-1 readout in 3T3-L1 cells

    PMID:27872488

    Open questions at the time
    • Direct PA binding site on mTORC1/DEPTOR not mapped
    • Single cell-line context
  8. 2017 Medium

    Broadened PLD1 trafficking roles to ER-to-Golgi COPII transport and autophagosome precursor membranes, with HS1BP3 identified as a negative regulator of PLD1 at ATG16L1 membranes.

    Evidence Cell-free COPII coat recruitment assay with PLD1 inhibition; HS1BP3 depletion with PLD activity, PA measurement, and PLD1 localization to ATG16L1 membranes (replicated in zebrafish)

    PMID:28318354 PMID:28648601

    Open questions at the time
    • How PA promotes Sec13/31 recruitment mechanistically unresolved
    • Mechanism of HS1BP3 inhibition of PLD1 not defined
  9. 2020 High

    Resolved the human PLD1 catalytic domain at high resolution, defining the active site, the essential PIP2-binding membrane interface, and the RhoA interaction surface.

    Evidence 1.8-A X-ray crystallography with active-site, PIP2-pocket, and RhoA-interface mutagenesis and activation assays

    PMID:32198492

    Open questions at the time
    • N-terminal PX/PH regulatory regions not captured in the structure
    • Membrane-bound conformational dynamics not resolved
  10. 2021 Medium

    Linked PLD1 loss-of-function to a human Mendelian disease, establishing catalytic activity as essential for cardiac valve development.

    Evidence Whole-exome sequencing of 30 patients from 21 families, enzymatic assays of mutant proteins, and EndMT assay with PLD1 inhibition

    PMID:33645542

    Open questions at the time
    • Downstream PA-dependent effectors in valvulogenesis not identified
    • Genotype-phenotype correlation across variants not fully resolved
  11. 2021 Medium

    Defined RalA as the upstream signal recruiting PLD1 to lysosomes during nutrient depletion to drive localized PA production and lipid-droplet growth.

    Evidence RalA inhibition, PLD1 knockout/inhibition, live-cell imaging of lysosomal recruitment, and perilipin 3 localization readout

    PMID:34320341

    Open questions at the time
    • Mechanism by which PA recruits PLIN3 not established
    • Single-lab system
  12. 2022 Medium

    Identified ARL11/ARL14 as preferred PLD1 GTPase partners, expanding the regulatory GTPase set and linking PLD1 to macrophage phagocytosis.

    Evidence miniTurboID proximity interactome, TMT quantitative MS, PLD1 activity assay, and phagocytosis assay

    PMID:35844135

    Open questions at the time
    • Structural basis of ARL11/14 vs Arf1 selectivity not determined
    • Whether PLD1 recruits ARL GTPases or vice versa not fully resolved
  13. 2024 Medium

    Revealed a PLD1 requirement in oocyte meiotic spindle assembly and MTOC clustering, mechanistically tying PA/PIP2 to cofilin phosphorylation and autophagy balance.

    Evidence Morpholino knockdown, PLD1 inhibitor, proximity ligation for direct spindle interactions, and PIP2/CFL1-S3E/ACTR2 rescue with autophagy manipulation

    PMID:38513669

    Open questions at the time
    • Direct PA/PIP2 effector at the MTOC not identified
    • Relationship between spindle and autophagic roles incompletely separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PLD1's distinct PA pools are spatially and temporally segregated to selectively engage trafficking, growth-signaling, and cytoskeletal effectors remains unresolved.
  • No structure of full-length regulated PLD1 with PX/PH domains
  • Direct PA-effector binding interfaces (mTORC1, AP2, COPII, PLIN3) not mapped
  • Mechanism distinguishing enzymatic from non-enzymatic scaffolding functions not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 3 GO:0140098 catalytic activity, acting on RNA 3 GO:0008289 lipid binding 2
Localization
GO:0005811 lipid droplet 3 GO:0005764 lysosome 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9612973 Autophagy 2 R-HSA-1430728 Metabolism 1
Partners
ARF1ARL11ARL14CFL1NPM1PEA15RHOARSK2

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Crystal structure of human PLD1 catalytic domain at 1.8 Å resolution reveals a globular fold with a funnel-shaped hydrophobic cavity leading to the active site, a PIP2-binding polybasic pocket at the membrane interface essential for activity, a C-terminus that contributes to the catalytic pocket, and a phosphohistidine intermediate. Mapping of mutations that disrupt RhoA activation identifies the RhoA-PLD1 binding interface. X-ray crystallography (1.8 Å resolution), active-site mutagenesis, PIP2-binding pocket mutagenesis, RhoA activation assays Nature chemical biology High 32198492
2003 PLD1 acts upstream of mTOR to regulate S6K1 activation and cell size. Catalytically inactive PLD1 exerts a dominant-negative effect on S6K1 activation; RNAi knockdown of PLD1 drastically inhibits serum-stimulated S6K1 activation and 4E-BP1 hyperphosphorylation. Cdc42 activates S6K1 through the mTOR pathway via a region specifically required for PLD1 activation, and exogenous phosphatidic acid (PA) rescues the effect of a PLD1-inactive Cdc42 mutant. RNAi knockdown, dominant-negative overexpression, rapamycin-resistant S6K1 mutant epistasis, exogenous PA rescue, kinase activity assays Current biology : CB High 14653992
2008 RSK2 directly phosphorylates PLD1 at Thr-147 in the N-terminal phox homology domain, activating PLD1 activity and promoting exocytosis in chromaffin cells. RSK2 is activated by calcium (high K+ stimulus), physically interacts with PLD1, and expression of a phosphomimetic PLD1-T147 mutant fully restores secretion in RSK2-depleted cells. Co-immunoprecipitation, site-directed mutagenesis (phosphomimetic mutant), RSK2 knockdown, PLD activity assay, chromaffin cell secretion assay Proceedings of the National Academy of Sciences of the United States of America High 18550821
2013 RSK2-dependent phosphorylation of PLD1 is required for NGF-induced neurite outgrowth and membrane supply via VAMP-7 vesicle fusion. A phosphomimetic PLD1 mutant rescues inhibition of neurite outgrowth in RSK2-silenced PC12 cells. TIRF microscopy shows RSK2 and PLD1 positively control VAMP-7 vesicle fusion at neurite growth sites. Neurons from Pld1 knockout mice show delayed growth similar to Rsk2 knockout neurons. siRNA knockdown, phosphomimetic PLD1 mutant rescue, TIRF microscopy, PLD activity assay, knockout mouse neurons The Journal of neuroscience : the official journal of the Society for Neuroscience High 24336713
2006 PLD1 (not PLD2) is the isoform responsible for cytosolic lipid droplet formation. PLD1 functions upstream of ERK2 in this pathway: inhibition of ERK2 eliminates the effect of PLD1 on lipid droplet formation without affecting PLD1 enzymatic activity. ERK2 increases phosphorylation of dynein and its accumulation on ADRP-containing lipid droplets; microinjection of anti-dynein antibodies strongly inhibits lipid droplet formation. siRNA knockdown, overexpression, microinjection, pharmacological inhibition, cell-free system, ERK2 epistasis Journal of cell science High 16723731
2000 PLD1 palmitoylation occurs on Cys240 and Cys241, requires N-terminal sequences (first 168 aa) and interdomain association of the two HKD halves. Palmitoylation-deficient PLD1 (C240A/C241A) retains basal activity and PKC responsiveness but shows markedly reduced Ser/Thr phosphorylation and weakened membrane association. Mutation of Cys310 or Cys612 increases basal PLD activity 2- or 4-fold, respectively. Site-directed mutagenesis, metabolic labeling (palmitoylation), membrane fractionation, in vitro PLD activity assay, PKC stimulation assay The Journal of biological chemistry High 11121416
2000 Human PLD1 can be activated by calcium-mobilizing agonists and by co-expression with PKCα (but not PKCδ), and PLD1 physically associates with PKC isoforms. Calcium enhances PLD1 activity in membrane assays. PLD1 activity is also stimulated by calmodulin and PKCα-enriched cytosol in reconstitution assays. Co-expression in Sf9 cells, immunoprecipitation, membrane reconstitution assay, PLD activity (transphosphatidylation), calcium ionophore treatment Biochimica et biophysica acta Medium 10838164
2005 PLD1 (but not PLD2) localizes to lipid droplets in oleic acid-treated NIH3T3 cells in an Arf1-dependent manner. Brefeldin A (an ARF-GEF inhibitor) suppresses both PLD activation and lipid droplet formation. Arf1 stimulates PLD1 activity in LD-enriched subcellular fractions. Immunocytochemistry, subcellular fractionation, Western blot, pharmacological inhibition (Brefeldin A), exogenous Arf1 stimulation, PLD activity assay Biochemical and biophysical research communications Medium 16054594
2010 PLD1 acts downstream of Src to activate PKCγ in VEGF signaling in retinal microvascular endothelial cells; the Src→PLD1→PKCγ cascade mediates VEGF-induced endothelial cell migration, proliferation, and tube formation, and is required for hypoxia-induced retinal neovascularization in vivo. Pharmacological inhibition, dominant-negative mutants, siRNA knockdown, in vivo retinal neovascularization model (oxygen-induced retinopathy) Blood Medium 20421451
2011 cPLA2 acts as an effector downstream of the Src→PLD1→PKCγ signaling axis; VEGF-induced cPLA2 phosphorylation and arachidonic acid release require Src, PLD1, and PKCγ activity, and exogenous AA rescues endothelial responses when cPLA2 is depleted. siRNA knockdown, pharmacological inhibition, AA rescue experiments, in vivo oxygen-induced retinopathy model The Journal of biological chemistry Medium 21536681
2006 PLD1 enzymatic activity mediates chemokine-induced (IL-8, FMLP) chemotaxis of HL-60 leukocytes; a lipase-inactive PLD1-K830R mutant abrogates all chemokine-induced potentiating actions, while chemokinesis does not require PLD1 enzymatic activity. Both PLD1 and PLD2 are required for cell motility and associate with cell polarity markers, F-actin, and adhesion structures. siRNA knockdown, overexpression of lipase-inactive mutant (K830R), in vitro PLD activity assay, chemokinesis/chemotaxis assays, immunofluorescence microscopy Blood Medium 16873675
2012 PLD1 acts downstream of RhoA to suppress dendritic branching in hippocampal neurons. The branching restriction by constitutively active RhoA (V14-RhoA) is partially rescued by PLD1 knockdown, and the inhibitory effect of both V14-RhoA and PLD1 overexpression can be ameliorated by reducing PA levels. Gain-of-function and loss-of-function (overexpression, siRNA), constitutively active RhoA epistasis, PA level manipulation, cultured hippocampal neurons The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 22674271
2009 PLD1 directly interacts with μ2 (a subunit of AP2 adaptor complex) and this interaction requires PLD1 binding to its own product phosphatidic acid. PLD1–μ2 interaction facilitates membrane recruitment of AP2 and determines the kinetics of EGFR endocytosis. Co-immunoprecipitation, kinetic analysis of endocytosis, AP2 membrane recruitment assay, PA-binding requirement demonstrated by mutagenesis/biochemical assay PloS one Medium 19763255
2010 PLD1 residues 762–801 (within the D4 domain, residues 712–818) constitute the minimal binding interface for PED/PEA15, with a Kd ~0.7 μM. PED/PEA15 interaction with PLD1 D4 enhances PKCα activity and impairs insulin-stimulated PKCζ activation and glucose transport; disruption of this interaction restores normal signaling. D4 deletion mutants, ELISA, surface plasmon resonance (SPR), transfection of D4α fragments, PKCα/PKCζ activity assay Molecular bioSystems Medium 20714510
2013 Disruption of PED/PEA15–PLD1 interaction in vivo (by adenoviral D4 delivery) decreases PKCα activation, restores PKCζ activation and insulin-dependent glucose uptake in skeletal muscle of PED/PEA15-overexpressing transgenic mice and in high-fat-diet obese mice. Adenoviral gene transfer, co-immunoprecipitation, PKC activity assay, glucose uptake assay, transgenic and HFD mouse models PloS one Medium 23585839
2016 PLD1 negatively regulates adipogenic differentiation by generating PA, which displaces DEPTOR from mTORC1, leading to mTOR-dependent phosphorylation of IRS-1 at Ser636/639 and suppression of insulin signaling required for adipogenesis. PLD1-specific inhibitor (VU0155069), siRNA knockdown, PA treatment, PLD1 overexpression, mTORC1 pull-down (DEPTOR displacement), phospho-IRS-1 Western blot, 3T3-L1 differentiation assay Scientific reports Medium 27872488
2021 RalA acts downstream of autophagy to recruit PLD1 to lysosomes during nutrient depletion, where PLD1 converts PC to PA to promote localized PA production. This recruits perilipin 3 (PLIN3) to expanding lipid droplets, facilitating LD growth. RalA inhibition, PLD1 knockout/inhibition, live-cell imaging of lysosomal PLD1 recruitment, perilipin 3 localization assay, nutrient depletion model Cell reports Medium 34320341
2017 PLD1 inhibition suppresses COPII vesicle transport from ER to Golgi by preventing Sec13/31 recruitment from the cytosol to the ER membrane during COPII vesicle formation. PLD1 knockdown increases ER stress marker GRP78 and promotes apoptosis. PLD1 inhibitor, siRNA knockdown, cell-free COPII coat protein recruitment assay, Western blot for ER stress markers Biochemical and biophysical research communications Medium 28648601
2017 HS1BP3 negatively regulates autophagy by inhibiting PLD1 activity and reducing PLD1 localization to ATG16L1-positive autophagosome precursor membranes, thereby decreasing PA content on these membranes. HS1BP3 depletion increases total cellular PA from elevated PLD activity and PLD1 localization to ATG16L1 membranes. HS1BP3 siRNA depletion, PLD activity assay, PA measurement, PLD1 localization (immunofluorescence), autophagosome formation assay Autophagy Medium 28318354
2022 PLD1 preferentially interacts with ARL11 and ARL14 (Arf GTPase family members); ARL11/14 activate PLD1 and may be recruited to membrane vesicles by PLD1. PLD1 and ARL11 collaborate to promote macrophage phagocytosis. Proximity labeling (miniTurboID) interactome, TMT-based quantitative MS, PLD1 activity assay, phagocytosis assay The EMBO journal Medium 35844135
2015 In cortical neurons, BDNF induces rapid RSK2-dependent PLD1 activation, and PLD1 is required for BDNF-stimulated ERK1/2-CREB and mTOR-S6K signaling. PLD1, ERK1/2, and RSK2 form a complex with scaffolding protein PEA15 after BDNF treatment and partially colocalize on endosomal structures. Pld1 and Rsk2 knockout neurons, PLD activity assay, immunofluorescence colocalization, PEA15 siRNA silencing, phospho-CREB nuclear accumulation assay Scientific reports Medium 26437780
2012 In acrosomal exocytosis, diacylglycerol activates PLD1 through PKC, and PLD1-generated PA promotes PIP2 synthesis in a positive feedback loop. Both PKC and PLD1 are required to maintain IP3-sensitive calcium channel opening required for exocytosis. Rescue experiments with PA, PIP2, and adenophostin confirm PLD1's role in maintaining PIP2 levels upstream of calcium channel gating. Permeabilized sperm exocytosis assay, PLD1 inhibition, PKC inhibition, PA/PIP2 rescue, Rab3A GTP-loading assay Biochimica et biophysica acta Medium 22609963
2019 PLD1 physically associates with PKD1 (protein kinase D1), and PLD1 acts upstream of PKD1 to positively regulate dendritic spine morphogenesis in hippocampal neurons. PLD1 inhibitor reduces PKD1 activation. Co-immunoprecipitation, siRNA knockdown with rescue, PLD1 inhibitor treatment, dendritic spine morphology analysis Molecular and cellular neurosciences Low 31356881
2013 The H452Y polymorphic form of the 5-HT2A receptor selectively reduces PLD1 binding to the receptor's carboxy-terminal tail and attenuates PLD signaling (but not Gq/11-PLC signaling). Co-immunoprecipitation and GST-fusion protein experiments show PLD1 docks to the 5-HT2AR C-terminal tail, and a blocking peptide spanning residue 452 reduces PLD1-dependent responses. Co-immunoprecipitation, GST-fusion pulldown, blocking peptides, PLD activity assay, cell proliferation assay Cellular signalling Low 23314176
2017 PLD1 negatively regulates the cofilin-p53 pro-apoptotic pathway by promoting cofilin inactivation and inhibiting cofilin/p53 complex formation, thereby preventing p53 mitochondrial and nuclear translocation. Cofilin knockdown or PLD1 overexpression inhibits this apoptotic pathway. Cofilin knockdown, PLD1 overexpression, immunofluorescence for p53 subcellular localization, co-immunoprecipitation of cofilin-p53 complex, APP/PS1 transgenic mice Scientific reports Low 28912445
2021 In hepatocellular carcinoma, cofilin 1 (CFL1) physically interacts with PLD1 and maintains PLD1 expression by inhibiting ubiquitin-mediated protein degradation, thereby activating AKT signaling. Hypoxia-induced CFL1 promotes tumor progression through the CFL1/PLD1/AKT axis. Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, AKT phosphorylation Western blot, xenograft model Clinical and translational medicine Low 33784016
2024 PLD1 is required for spindle assembly, MTOC clustering, and cortical spindle migration in mouse oocyte meiosis. PLD1 interacts directly with spindle components, RAB11A+ vesicles, and autophagic vacuoles. PLD1 suppression decreases PIP2, phospho-cofilin (p-CFL1-Ser3), and ACTR2 on MTOC/spindle; exogenous PIP2 or CFL1-S3E (hyperphosphorylation mutant) partially rescues spindle defects. Autophagy activation phenocopies PLD1 loss, and autophagy inhibition rescues PLD1-depleted oocytes by restoring PIP2, ACTR2, and p-CFL1. Morpholino knockdown, PLD1 inhibitor, proximity ligation assay (direct spindle interaction), exogenous PIP2/CFL1-S3E/ACTR2 rescue, autophagy manipulation, immunofluorescence Autophagy Medium 38513669
2016 PLD1 is required for Frizzled7 (Fz7) receptor endocytosis in Xenopus embryos upon Wnt11 stimulation. PLD1 promotes Wnt/PCP signaling activation through its PX domain, which regulates GAP activity of dynamin to facilitate Fz7 endocytosis. Loss- and gain-of-function of PLD1 disrupts convergent extension movements in Xenopus gastrulation. Loss/gain-of-function in Xenopus embryos, biochemical analysis of Fz7 endocytosis, live imaging, dynamin GAP assay, PX domain mutants Developmental biology Medium 26806705
2024 Nuclear PLD1 interacts with nucleophosmin 1 (NPM1) through a non-enzymatic mechanism, triggering NPM1 nuclear translocation. Nuclear NPM1 acts as a transcription factor to upregulate IL7R expression, which activates JAK1/STAT5/BCL-2 signaling to confer gemcitabine resistance in pancreatic cancer. CRISPRa/dCas9 genome-wide screen, co-immunoprecipitation (Co-IP), ChIP, ChIP-seq, transcriptome sequencing, PLD1 inhibitor (VU0155069) Cancer biology & medicine Medium 37381714
2004 In porcine tracheal smooth muscle cells, ACh/PMA stimulation induces tyrosine phosphorylation of PLD1 (not PLD2) through a PKC- and tyrosine kinase-dependent pathway. Both ACh and PMA increase Ser/Thr and Tyr phosphorylation of PLD1, blocked by PKC inhibitor calphostin C or tyrosine kinase inhibitor genistein. Western blot with anti-phosphotyrosine antibodies, pharmacological inhibitors (genistein, calphostin C), PLD activity assay Journal of biomedical science Low 15591778
2021 PLD1 loss-of-function mutations cause congenital right-sided cardiac valve defects. Missense variants in PLD1 are overrepresented in regions critical for catalytic activity, and most mutant proteins show strongly reduced enzymatic activity. PLD1 inhibition decreases endothelial-mesenchymal transition (EndMT), an early step in valvulogenesis. Whole-exome sequencing, enzymatic activity assay of mutant PLD1 proteins, EndMT assay with PLD1 inhibitor, analysis of 30 patients from 21 families The Journal of clinical investigation Medium 33645542
2024 PLD1 promotes nasopharyngeal carcinoma progression via a positive feedback loop with NF-κB: PLD1 enhances NF-κB activity by facilitating phosphorylation and nuclear translocation of RELA, which in turn binds the PLD1 promoter and augments PLD1 expression. ChIP assay (RELA binding to PLD1 promoter), RELA knockdown/overexpression rescue, PLD1 inhibitor (VU0155069) in patient-derived xenograft, luciferase reporter Journal of genetics and genomics = Yi chuan xue bao Low 38885836
2017 T. gondii GRA7-III interacts with the PX domain of PLD1, facilitating PLD1 enzymatic activity, phago-lysosomal maturation, and antimicrobial activity in a GRA7-III Ser135 phosphorylation-dependent manner via PKCα. Co-immunoprecipitation, PLD1 enzymatic activity assay, phago-lysosomal maturation assay, PKCα phosphorylation experiments PLoS pathogens Low 28125719

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 PLD1 and ERK2 regulate cytosolic lipid droplet formation. Journal of cell science 140 16723731
2003 PLD1 regulates mTOR signaling and mediates Cdc42 activation of S6K1. Current biology : CB 140 14653992
2006 Phagocyte cell migration is mediated by phospholipases PLD1 and PLD2. Blood 81 16873675
1997 Identification of a novel Ca2+-dependent, phosphatidylethanolamine-hydrolyzing phospholipase D in yeast bearing a disruption in PLD1. The Journal of biological chemistry 71 8995222
2000 Regulation of human PLD1 and PLD2 by calcium and protein kinase C. Biochimica et biophysica acta 60 10838164
2021 Hypoxia-induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway. Clinical and translational medicine 48 33784016
2020 Crystal structure of human PLD1 provides insight into activation by PI(4,5)P2 and RhoA. Nature chemical biology 45 32198492
2012 Diacylglycerol stimulates acrosomal exocytosis by feeding into a PKC- and PLD1-dependent positive loop that continuously supplies phosphatidylinositol 4,5-bisphosphate. Biochimica et biophysica acta 42 22609963
2008 The Coffin-Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1. Proceedings of the National Academy of Sciences of the United States of America 42 18550821
2005 Arf1-dependent PLD1 is localized to oleic acid-induced lipid droplets in NIH3T3 cells. Biochemical and biophysical research communications 42 16054594
2016 Congenital valvular defects associated with deleterious mutations in the PLD1 gene. Journal of medical genetics 41 27799408
2013 The Coffin-Lowry syndrome-associated protein RSK2 regulates neurite outgrowth through phosphorylation of phospholipase D1 (PLD1) and synthesis of phosphatidic acid. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 24336713
2007 PLD1 is overexpressed in an ER-negative MCF-7 cell line variant and a subset of phospho-Akt-negative breast carcinomas. British journal of cancer 39 17726467
2020 Promotion of cell autophagy and apoptosis in cervical cancer by inhibition of long noncoding RNA LINC00511 via transcription factor RXRA-regulated PLD1. Journal of cellular physiology 35 32067228
2010 PLD1-dependent PKCgamma activation downstream to Src is essential for the development of pathologic retinal neovascularization. Blood 35 20421451
2013 Both Kdr and Flt1 play a vital role in hypoxia-induced Src-PLD1-PKCγ-cPLA(2) activation and retinal neovascularization. Blood 34 23319572
2011 PLD1 rather than PLD2 regulates phorbol-ester-, adhesion-dependent and Fc{gamma}-receptor-stimulated ROS production in neutrophils. Journal of cell science 34 21610093
2017 Toxoplasma gondii GRA7-Targeted ASC and PLD1 Promote Antibacterial Host Defense via PKCα. PLoS pathogens 27 28125719
2017 Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation. Scientific reports 27 28912445
2020 MiR-122-5p and miR-326-3p promote cadmium-induced NRK-52E cell apoptosis by downregulating PLD1. Environmental toxicology 26 32697411
2021 Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy. The Journal of clinical investigation 24 33645542
2021 RalA and PLD1 promote lipid droplet growth in response to nutrient withdrawal. Cell reports 24 34320341
2015 PLD1 participates in BDNF-induced signalling in cortical neurons. Scientific reports 24 26437780
2021 PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer. Cancer letters 23 33945837
2020 PLD1 and PLD2 differentially regulate the balance of macrophage polarization in inflammation and tissue injury. Journal of cellular physiology 23 33368247
2022 Defining the proximal interaction networks of Arf GTPases reveals a mechanism for the regulation of PLD1 and PI4KB. The EMBO journal 22 35844135
2016 PLD1 regulates adipogenic differentiation through mTOR - IRS-1 phosphorylation at serine 636/639. Scientific reports 21 27872488
2012 PLD1 Negatively Regulates Dendritic Branching. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 22674271
2011 Activation of cytosolic phospholipase A2 downstream of the Src-phospholipase D1 (PLD1)-protein kinase C γ (PKCγ) signaling axis is required for hypoxia-induced pathological retinal angiogenesis. The Journal of biological chemistry 20 21536681
2001 Presence of a phospholipase D (PLD) distinct from PLD1 or PLD2 in human neutrophils: immunobiochemical characterization and initial purification. Biochimica et biophysica acta 20 11341962
2000 Requirements and effects of palmitoylation of rat PLD1. The Journal of biological chemistry 19 11121416
2024 PLD1 is a key player in cancer stemness and chemoresistance: Therapeutic targeting of cross-talk between the PI3K/Akt and Wnt/β-catenin pathways. Experimental & molecular medicine 17 38945955
2017 Inhibition of PLD1 activity causes ER stress via regulation of COPII vesicle formation. Biochemical and biophysical research communications 17 28648601
2015 Vps34 and PLD1 take center stage in nutrient signaling: their dual roles in regulating autophagy. Cell communication and signaling : CCS 17 26589724
2019 Aflatoxin B1 induces S phase arrest by upregulating the expression of p21 via MYC, PLK1 and PLD1. Biochemical pharmacology 15 31075264
2021 PLD1 knockdown reduces metastasis and inflammation of fibroblast-like synoviocytes in rheumatoid arthritis by modulating NF-κB and Wnt/β-catenin pathways. Autoimmunity 13 34431424
2010 Residues 762-801 of PLD1 mediate the interaction with PED/PEA15. Molecular bioSystems 13 20714510
2014 PED/PEA-15 inhibits hydrogen peroxide-induced apoptosis in Ins-1E pancreatic beta-cells via PLD-1. PloS one 12 25489735
2024 PLD1 promotes spindle assembly and migration through regulating autophagy in mouse oocyte meiosis. Autophagy 10 38513669
2017 Tissue microarray staining reveals PLD1 and Sp1 have a collaborative, pro-tumoral effect in patients with osteosarcomas. Oncotarget 10 29088790
2013 Adenoviral gene transfer of PLD1-D4 enhances insulin sensitivity in mice by disrupting phospholipase D1 interaction with PED/PEA-15. PloS one 10 23585839
2008 Expression and purification of the D4 region of PLD1 and characterization of its interaction with PED-PEA15. Protein expression and purification 10 18420420
2023 Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma. Cancer biology & medicine 9 37381714
2022 Dickkopf1 (Dkk1) Alleviates Vascular Calcification by Regulating the Degradation of Phospholipase D1 (PLD1). Journal of cardiovascular translational research 9 35426038
2019 PLD1 promotes dendritic spine morphogenesis via activating PKD1. Molecular and cellular neurosciences 9 31356881
2017 HS1BP3 inhibits autophagy by regulation of PLD1. Autophagy 9 28318354
2009 Determination of EGFR endocytosis kinetic by auto-regulatory association of PLD1 with mu2. PloS one 9 19763255
2017 PLD1 overexpression promotes invasion and migration and function as a risk factor for Chinese glioma patients. Oncotarget 8 28915652
2016 PLD1 regulates Xenopus convergent extension movements by mediating Frizzled7 endocytosis for Wnt/PCP signal activation. Developmental biology 8 26806705
2023 OGD/R-induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation. Cell biochemistry and function 7 37691020
2019 MicroRNA-638 expression change in osteosarcoma patients via PLD1 and VEGF expression. Experimental and therapeutic medicine 7 30988774
2013 Attenuated PLD1 association and signalling at the H452Y polymorphic form of the 5-HT(2A) receptor. Cellular signalling 5 23314176
2024 A positive feedback loop between PLD1 and NF-κB signaling promotes tumorigenesis of nasopharyngeal carcinoma. Journal of genetics and genomics = Yi chuan xue bao 4 38885836
2022 Characterization of Plocamium telfairiae Extract-Functionalized Au Nanostructures and Their Anti-Adipogenic Activity through PLD1. Marine drugs 4 35877714
2020 Treatment with Gold Nanoparticles Using Cudrania tricuspidata Root Extract Induced Downregulation of MMP-2/-9 and PLD1 and Inhibited the Invasiveness of Human U87 Glioblastoma Cells. International journal of molecular sciences 3 32074974
2025 Exosome-Mediated Delivery of a PLD1 Modulator Overcomes Bioavailability Hurdles to Target Synaptopathy in Neurodegenerative Diseases. Pharmaceutical research 2 41087673
2023 Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report. Journal of medical case reports 2 37770978
2021 PLD1 promotes reactive oxygen species production in vascular smooth muscle cells and injury-induced neointima formation. Biochimica et biophysica acta. Molecular and cell biology of lipids 2 34610470
2020 Association of Variants in PLD1, 3p24.1, and 10q11.21 Regions With Hirschsprung's Disease in Han Chinese Population. Frontiers in genetics 2 32765588
2004 Regulation of acetylcholine-induced phosphorylation of PLD1 in porcine tracheal smooth muscle. Journal of biomedical science 2 15591778
2025 Dual Role for Pld1 in Klebsiella pneumoniae Virulence: Transcriptomics and Proteomics Provide Insights into Direct and Indirect Effects. Journal of proteome research 1 40396329
2025 PLD1-Dependent Regulation of Synaptic Integrity: Implications for Cognitive Resilience and Alzheimer's Disease Pathogenesis. bioRxiv : the preprint server for biology 1 41777445
2024 Prenatal detection of novel compound heterozygous variants of the PLD1 gene in a fetus with congenital heart disease. Frontiers in genetics 1 39553471
2024 Segetalin B promotes bone formation in ovariectomized mice by activating PLD1/SIRT1 signaling to inhibit γ-secretase-mediated Notch1 overactivation. The Journal of steroid biochemistry and molecular biology 1 39736459
2020 Blockade of PLD1 potentiates the antitumor effects of bortezomib in multiple myeloma cells by inhibiting the mTOR/NF-κB signal pathway. Hematology (Amsterdam, Netherlands) 1 33191863
2015 PLD1 activation mediates Amb a 1-induced Th2-associated cytokine expression via the JNK/ATF-2 pathway in BEAS-2B cells. Cellular immunology 1 26302934
2026 Exploring the PLD1-tau interaction in Frontotemporal Dementia. bioRxiv : the preprint server for biology 0 41726972
2026 PLD1 and PLD2 promote an immunosuppressive tumor microenvironment via CCL19-dependent macrophage polarization and PD-L1 induction. Experimental & molecular medicine 0 42243532
2025 RETRACTION: Promotion of Cell Autophagy and Apoptosis in Cervical Cancer by Inhibition of Long Noncoding RNA LINC00511 via Transcription Factor RXRA-regulated PLD1. Journal of cellular physiology 0 39888011
2025 Total saponins from Panax japonicus inhibit phosphatidylcholine hydrolysis and relieve hepatic steatosis via the miR-1a-3p/PLD1 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 40663939
2025 miR-21 regulates LPS-induced apoptosis and inflammatory injury in rat cardiomyocytes by targeting PLD1 and STAT3. Polish journal of pathology : official journal of the Polish Society of Pathologists 0 40977551
2024 Pathogenic single nucleotide polymorphisms in RhoA gene: Insights into structural and functional impacts on RhoA-PLD1 interaction through molecular dynamics simulation. Current research in structural biology 0 39698059

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