Affinage

PLD2

Phospholipase D2 · UniProt O14939

Length
933 aa
Mass
106.0 kDa
Annotated
2026-04-28
68 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLD2 is a dual-function signaling enzyme that generates phosphatidic acid (PA) through phosphatidylcholine hydrolysis and independently acts as a guanine nucleotide exchange factor (GEF) for Rac2 and Cdc42 via its PX and PH domains, linking lipid signaling to cytoskeletal remodeling, vesicle trafficking, and cell migration (PMID:22106281, PMID:23035122, PMID:41223946). PLD2 lipase activity is regulated by PIP2 generated through its physical interaction with Type Iα PIP kinase (PMID:11032811), and by phosphorylation events including EGF receptor-mediated Y11 phosphorylation (PMID:9837959), Cdk5-mediated S134 phosphorylation (PMID:18625302), JAK3-mediated Y415 phosphorylation (PMID:21414324), and Grb2 binding at Y169/Y179 (PMID:16407827), while oleate-induced S-acylation at Cys223/224 modulates both lipase and GEF activities by redistributing PLD2 from lipid rafts to PIP2-enriched membrane domains (PMID:41223946). PA produced by PLD2 functions as a critical second messenger that activates mTORC1 through a direct PLD2–raptor complex (PMID:16837165), recruits KIF5B to vesicles for MT1-MMP surface delivery and cancer invasion (PMID:29033361), binds IQGAP1 to drive cell migration (PMID:30811216), and regulates tight junction integrity via c-Src-dependent occludin degradation (PMID:28484281). PLD2 also serves as a plasma membrane tension sensor that controls actin nucleation through mTORC2 in neutrophil chemotaxis (PMID:27280401), mediates ARF6-dependent exosome biogenesis (PMID:24637612), and couples to IL-4R/JAK3 signaling to promote M2 macrophage polarization (PMID:33368247).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1998 High

    Establishing PLD2 as an EGF receptor-proximal signaling enzyme resolved how growth factor receptors directly regulate phospholipase D activity, revealing constitutive EGFR–PLD2 association and inhibitory Y11 phosphorylation as an activation switch.

    Evidence Co-IP, Y11F mutagenesis, and lipase activity assays in HEK293 cells

    PMID:9837959

    Open questions at the time
    • Whether Y11 phosphorylation regulates PLD2 in vivo
    • Identity of the phosphatase that removes pY11
  2. 2000 High

    Demonstrating that PLD2 activity in vivo depends on local PIP2 generated by a physically associated Type Iα PIP kinase resolved how PLD2 is regulated at steady state and defined a feed-forward lipid signaling module.

    Evidence Reciprocal co-IP and in vivo activity assays in COS7 cells

    PMID:11032811

    Open questions at the time
    • Structural basis of the PLD2–PIPKIα interaction
    • Whether other PIP kinase isoforms substitute
  3. 2000 Medium

    Identifying PKCα as a direct activator and physical interactor of PLD2 placed PLD2 downstream of calcium/DAG signaling, expanding the upstream inputs beyond receptor tyrosine kinases.

    Evidence Co-expression in Sf9 cells, IP, and membrane reconstitution assays

    PMID:10838164

    Open questions at the time
    • PKCα phosphorylation site on PLD2 not identified
    • Single reconstitution system
  4. 2004 High

    Showing that alpha-synuclein inhibits PLD2 in vitro through its alpha-helical domain, with inhibition abolished by disease-relevant phosphorylations, linked PLD2 to potential Parkinson's disease-relevant lipid signaling.

    Evidence Reconstituted in vitro PLD2 activity assay with systematic alpha-synuclein mutants

    PMID:15033366

    Open questions at the time
    • No in vivo or cellular validation of alpha-synuclein–PLD2 inhibition
    • Physiological relevance in neurons unclear
  5. 2006 High

    Identifying a direct PLD2–raptor complex mediated by a TOS-like motif and showing that both lipase activity and raptor binding are required for mTOR activation established PLD2 as a PA-dependent upstream activator of mTORC1.

    Evidence Co-IP, TOS motif mutagenesis, lipase-dead mutants, S6K1/4EBP1 phosphorylation in cells

    PMID:16837165

    Open questions at the time
    • Structural detail of PA–mTOR interaction
    • Relative contribution of PLD2 vs PLD1 to mTOR in different tissues
  6. 2006 High

    Demonstrating that PLD2 lipase activity is essential for leukocyte chemotaxis and F-actin polarization answered whether PLD2 plays an effector role in immune cell migration.

    Evidence siRNA knockdown and lipase-dead mutant overexpression with chemotaxis and immunofluorescence in leukocytes

    PMID:16873675

    Open questions at the time
    • Whether GEF activity also contributes to chemotaxis at this point was unknown
  7. 2006 High

    Mapping two SH2 binding sites (Y169, Y179) for Grb2 on PLD2, with Y169 controlling lipase activity and Y179 controlling PLD2 phosphorylation state, defined how the adaptor Grb2 serves as a master regulator coupling PLD2 to both enzymatic activation and Ras/MAPK proliferative signaling.

    Evidence GST pull-down, co-IP, point mutants, ERK phosphorylation, and DNA synthesis assays

    PMID:16407827 PMID:17276458 PMID:21419846

    Open questions at the time
    • Whether both Grb2 SH2 sites are engaged simultaneously or sequentially
    • No structural model of PLD2–Grb2 complex
  8. 2008 High

    Identifying Cdk5-mediated S134 phosphorylation as necessary for EGF-dependent PLD2 activation placed PLD2 at an intersection of cell-cycle kinase and growth factor signaling, with functional consequence for insulin secretion.

    Evidence In vitro kinase assay, S134A mutagenesis, roscovitine inhibition, insulin secretion readout in beta cells

    PMID:18625302

    Open questions at the time
    • Whether S134 phosphorylation modulates GEF activity
    • In vivo relevance in pancreatic islets
  9. 2011 High

    Discovering that PLD2 functions as a GEF for Rac2 through its PX/PH domains — independent of lipase activity — fundamentally revised PLD2's identity from a pure lipase to a bifunctional enzyme coordinating lipid signaling and Rho-family GTPase activation.

    Evidence Reconstituted in vitro GEF assay, FRET in living cells, Kd determination (~3 nM), systematic mutagenesis of CRIB motifs and PX domain

    PMID:21378159 PMID:22106281 PMID:23035122

    Open questions at the time
    • No crystal structure of PX domain bound to Rac2
    • Whether PLD2 GEF activity is regulated by the same phosphorylations as lipase activity
  10. 2011 High

    Showing that JAK3 phosphorylates PLD2 at Y415 via a STAT-independent pathway to enable cancer cell invasion identified a new kinase input linking cytokine receptor signaling directly to PLD2-driven invasion.

    Evidence In vitro kinase assay, Y415 mutagenesis, siRNA, Matrigel invasion

    PMID:21414324

    Open questions at the time
    • Whether JAK3–PLD2 axis operates in non-cancer cells
    • No in vivo validation
  11. 2014 High

    Demonstrating that ARF6 and PLD2 regulate syntenin-dependent exosome biogenesis by controlling ILV budding into MVBs revealed a lipid-driven mechanism for exosome production distinct from ESCRT-dependent pathways.

    Evidence siRNA, dominant-negative mutants, EM quantification, and functional rescue

    PMID:24637612

    Open questions at the time
    • Whether PA itself or a PA metabolite drives ILV budding
    • Generalizability beyond syntenin cargo
  12. 2016 High

    Identifying PLD2 as a membrane tension sensor that limits actin nucleation through mTORC2 in neutrophils established a mechanotransduction pathway linking physical membrane properties to cell polarity and chemotaxis.

    Evidence Genetic knockout, optogenetic membrane tension manipulation, mathematical modeling, live-cell imaging

    PMID:27280401

    Open questions at the time
    • How PLD2 senses tension mechanistically at the molecular level
    • Whether mTORC2 is the sole effector
  13. 2017 High

    Showing that PLD2-generated PA directly binds KIF5B and is required for MT1-MMP vesicle trafficking, invadopodia formation, and metastasis identified a specific PA effector mediating PLD2's pro-invasive function.

    Evidence PLD2 knockout mice (MMTV-Neu), liposome pull-down, KIF5B mutagenesis, in vitro binding

    PMID:29033361

    Open questions at the time
    • PA-binding site on KIF5B not structurally resolved
    • Whether other kinesin family members also bind PA
  14. 2017 High

    Demonstrating that PLD2 disrupts tight junctions via c-Src-mediated occludin phosphorylation and proteasomal degradation, with intestinal Pld2 knockout mice protected from colitis, established PLD2 as a pathogenic mediator of epithelial barrier breakdown.

    Evidence Conditional Pld2 knockout mice, DSS colitis model, Western blot, proteasome inhibitor rescue

    PMID:28484281

    Open questions at the time
    • How PLD2 activates c-Src
    • Whether PA or GEF activity mediates tight junction disruption
  15. 2019 High

    Identifying PA-dependent IQGAP1 plasma membrane recruitment as a PLD2 effector pathway in VSMC migration and neointimal formation provided a scaffold-mediated mechanism for PLD2's role in vascular remodeling.

    Evidence PLD2 knockout mice (carotid ligation), PA-IQGAP1 binding assay, PA-binding-deficient IQGAP1 mutant rescue

    PMID:30811216

    Open questions at the time
    • Structural basis of PA–IQGAP1 binding
    • Whether PLD2–IQGAP1 axis operates in non-vascular contexts
  16. 2020 High

    Demonstrating isoform-specific coupling of PLD2 to IL-4R/JAK3 for M2 macrophage polarization (versus PLD1/TLR4 for M1) resolved how two PLD isoforms play opposing immunomodulatory roles.

    Evidence Isoform-specific macrophage-targeted knockouts (Pld2-LyzCre), co-IP, cytokine assays, in vivo sepsis and injury models

    PMID:33368247

    Open questions at the time
    • Mechanistic basis of PLD2's selective coupling to IL-4R
    • Whether PLD2 GEF activity contributes to M2 polarization
  17. 2025 High

    Discovering that oleate-induced S-acylation at Cys223/224 redistributes PLD2 from lipid rafts to PIP2-enriched domains and activates both lipase and GEF (toward Cdc42) activities revealed a fatty acid–responsive post-translational switch coordinating PLD2's dual functions.

    Evidence S-acylation assay, Cys223/224 mutagenesis, lipid raft isolation, GEF activity assay, confocal microscopy

    PMID:41223946

    Open questions at the time
    • Identity of the acyltransferase(s) responsible
    • Whether other fatty acids similarly regulate PLD2 S-acylation
    • In vivo metabolic relevance

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of PLD2's bifunctional catalysis — how the same protein independently catalyzes phospholipid hydrolysis and GEF activity — remains unresolved, as no high-resolution structure of full-length PLD2 or its complexes with Rac2/Cdc42 is available.
  • No crystal or cryo-EM structure of full-length PLD2
  • How lipase and GEF activities are coordinated in real time during signaling
  • Whether PLD2 tension sensing involves a conformational change or clustering mechanism

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 7 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 6 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1500931 Cell-Cell communication 2
Partners
EGFRGRB2IQGAP1JAK3KIF5BPIP5K1ARAC2RPTOR
Complex memberships
PLD2–Grb2 complexPLD2–PIPKIα complexPLD2–raptor–mTORC1 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 ARF6 and its effector PLD2 regulate syntenin exosome biogenesis by controlling the budding of intraluminal vesicles (ILVs) into multivesicular bodies (MVBs), identifying a novel pathway for ILV budding and exosome production. siRNA knockdown, dominant-negative mutants, electron microscopy, functional rescue experiments Nature Communications High 24637612
2016 Elevated membrane tension acts through PLD2 and mTORC2 to limit actin nucleation in neutrophils; loss of this pathway causes larger leading edges, higher membrane tension, and defective chemotaxis. Genetic knockdown/knockout, optogenetic membrane tension manipulation, mathematical modeling, live-cell imaging PLoS Biology High 27280401
2000 PLD2 physically interacts with Type Iα PIPkinase; PLD2 recruits PIPkinase to its intracellular location and its activity in vivo is regulated solely by local PtdIns(4,5)P2 levels generated by this kinase. Co-immunoprecipitation, overexpression in COS7 cells, in vivo activity assays The EMBO Journal High 11032811
1998 PLD2 (but not PLD1) constitutively associates with the EGF receptor in a ligand-independent manner and is tyrosine-phosphorylated at Tyr-11 upon EGF receptor activation; mutation Y11F enhances basal PLD2 activity ~2-fold. Co-immunoprecipitation, site-directed mutagenesis, transient transfection in HEK293 cells, lipase activity assay Journal of Biological Chemistry High 9837959
2004 Alpha-synuclein inhibits PLD2 in vitro; inhibition requires an alpha-helical conformation stabilized by exon 4 residues and residues in exon 6 (C-terminal 130–140); phosphorylation at S129, Y125, or Y136 abolishes PLD2 inhibition by alpha-synuclein. In vitro PLD2 activity assay with recombinant proteins, deletion and point mutants of alpha-synuclein, phosphomimetic mutations Journal of Molecular Biology High 15033366
2006 PLD2 forms a functional complex with mTOR/raptor via a TOS-like motif (Phe-Glu-Val-Gln-Val, aa 265–269) in PLD2; PLD2-dependent mTOR activation requires both binding to raptor and lipase activity, as lipase-inactive PLD2 cannot activate mTOR despite binding raptor. siRNA knockdown, co-immunoprecipitation, site-directed mutagenesis, S6K1/4EBP1 phosphorylation assays Cellular Signalling High 16837165
2006 PLD2 is required for leukocyte chemotaxis; PLD2 enzymatic activity mediates ENA-78/CXCR-2-induced chemotaxis, and both PLD2 isoforms associate with cell polarity and F-actin polymerization in response to IL-8. siRNA knockdown, overexpression of lipase-inactive mutant, in vitro chemotaxis assay, immunofluorescence microscopy Blood High 16873675
2000 PLD2 can be activated by calcium-mobilizing agonists and by co-expression with PKCα (but not PKCδ) in Sf9 cells; PLD1 and PLD2 physically associate with PKC isoforms and can be stimulated by calmodulin and PKCα-enriched cytosol in reconstitution assays. Co-expression in Sf9 cells, immunoprecipitation, membrane reconstitution assays, PtdEth production assay Biochimica et Biophysica Acta Medium 10838164
2004 VEGFR-2 and PLD2 co-localize in endothelial caveolae; VEGF activates PLD via VEGFR-2/PKC-δ, and PLD-generated phosphatidic acid is required for VEGF-induced MEK/ERK phosphorylation and endothelial cell proliferation. Subcellular fractionation, 1-butanol inhibition, phosphatidic acid rescue, pharmacological inhibitors, caveolae disruption with MβCD American Journal of Physiology Heart and Circulatory Physiology Medium 14704231
2011 PLD2 directly binds to Rac2 and functions as a guanine nucleotide exchange factor (GEF), promoting GDP dissociation (~72% decrease) and GTP association (~300% increase) on Rac2; GEF activity is independent of lipase activity. The PLD2-Rac2 interaction involves CRIB-region residues 263–266 in the PH domain and the PX domain of PLD2, and Switch-1 residue N17 of Rac2. In vitro GEF assay with recombinant proteins, co-immunoprecipitation, site-directed mutagenesis, FRET in living cells, cell functional assays (adhesion, chemotaxis, phagocytosis) PNAS High 22106281
2011 PLD2 co-localizes with Grb2 and actin-rich membrane protrusions in macrophages; PLD2 interacts with Grb2 via Y169 (SH2 domain), which enhances PLD activity and, together with Rac2, drives actin polymerization and membrane ruffle formation. YFP/CFP fluorescent chimeras, immunoprecipitation, site-directed mutagenesis (Y169F, Grb2-R86K), overexpression, actin polymerization assay Cellular Signalling High 21419846
2006 PLD2 residues Y169 and Y179 form two SH2 binding sites for Grb2: Y169 modulates enzymatic activity and Y179 regulates tyrosine phosphorylation of PLD2; Y169 also mediates cellular proliferation through Ras/MAPK when Y179 regulation is released. GST pull-down, co-immunoprecipitation, deletion and point mutants, DNA synthesis assay, ERK phosphorylation Oncogene High 16407827
2007 Grb2 is essential for PLD2 activity in vivo; Grb2 interacts with PLD2 via its SH2 domain (PLD2-Y169), and after EGF stimulation, Grb2 re-localizes PLD2 to Golgi-like perinuclear structures via its SH2 domain. shRNA stable knockdown, rescue with shRNA-resistant Grb2, co-immunoprecipitation, immunofluorescence microscopy, primary HUVEC imaging Journal of Molecular Biology High 17276458
2005 PLD2 exists in a ternary complex with protein tyrosine phosphatase PTP1B and the adaptor Grb2; PTP1B paradoxically increases both PLD2 lipase activity and tyrosine phosphorylation. Co-immunoprecipitation, recombinant PTP1B treatment of immunoprecipitates, phosphatase activity assay Biochemical and Biophysical Research Communications Medium 15896299
2008 Cdk5 phosphorylates PLD2 at Ser134; this phosphorylation is required for EGF-dependent PLD2 activation and insulin secretion in pancreatic beta cells; PLD2-S134A mutant fails to show EGF-dependent activation. In vitro kinase assay, dominant-negative Cdk5, pharmacological inhibition (roscovitine), site-directed mutagenesis, insulin secretion assay Cellular Signalling High 18625302
2011 JAK3 phosphorylates PLD2 at Y415, activating it and enabling EGF-stimulated cancer cell invasion; JAK3 operates via a STAT-independent pathway to activate PLD2. siRNA knockdown, in vitro kinase assay, site-directed mutagenesis (Y415), Matrigel invasion assay Journal of Molecular Biology High 21414324
2011 PLD2 has two CRIB motifs (CRIB-1 and CRIB-2) in and around the PH domain that mediate specific binding to Rac2; binding affinity Kd ~3 nM; PLD2 preferentially binds Rac2-GTP over Rac2-GDP; high Rac2-GTP acts as a termination signal inhibiting PLD2. Co-immunoprecipitation, FRET in living cells, in vitro binding with recombinant proteins, saturation binding assay, deletion mutagenesis Journal of Biological Chemistry High 21378159
2012 The PLD2 GEF catalytic site is located in the PX domain, formed by a hydrophobic pocket of residues Phe-107, Phe-129, Leu-166, Leu-173, and Arg-172; the PH domain region Ile-306–Ala-310 assists GEF activity by docking Rac2. PX domain alone is sufficient for GEF activity. In vitro GEF assay with GST fusion proteins and recombinant proteins, mutagenesis, chemotaxis and phagocytosis assays Journal of Biological Chemistry High 23035122
2009 Phosphorylated PLD2 (via Grb2 binding) mediates lipase activity, whereas dephosphorylated PLD2 (associated with CD45 phosphatase) drives cell proliferation; key residues are Y179 and Y511. Affinity-purified PLD2 is activated by Grb2 and deactivated by CD45 in vitro. siRNA for CD45, overexpression of PLD2 mutants, in vitro activation/deactivation assay, proliferation markers (PCNA, p27, phospho-histone-3) Biochemical and Biophysical Research Communications Medium 19715678
2017 PLD2-generated phosphatidic acid (PA) directly and specifically binds to KIF5B (kinesin-1 heavy chain) C-terminus; this PA-KIF5B interaction is required for vesicular association of KIF5B and surface localization of MT1-MMP, invadopodia formation, and breast cancer invasion/metastasis. PLD2 knockout mice (MMTV-Neu model), liposome pull-down screen, in vitro PA binding assay, KIF5B mutagenesis, live-cell imaging, invasion assay Developmental Cell High 29033361
2018 PLD2 (but not PLD1) is required for phagocytosis of aggregated oxidized LDL in macrophages; PLD2 and CD36 are mutually dependent for Agg-Ox-LDL uptake, and PLD2 couples phagocytosis with WASP, Grb2, and Actin complex formation. PLD2 knockout bone marrow-derived macrophages, PLD2-selective inhibitor, co-immunoprecipitation, phagocytosis assay Journal of Leukocyte Biology High 29656494
2016 RalA activates PLD2 in endothelial cells; PLD2-generated PA facilitates caveolae-mediated endocytosis and fusion of caveolae with the plasma membrane, as shown by a PA biosensor colocalizing with Cav-1. siRNA knockdown of RalA and PLD2, co-immunoprecipitation, GFP-PASS PA biosensor, TIRF microscopy, fluorescent BSA uptake assay, dominant-negative PLD2 Journal of Biological Chemistry High 27510034
2019 An acute decrease in plasma membrane tension activates PLD2 via disintegration of PLD2 nanodomains, leading to PA production, PI(4,5)P2- and F-actin-enriched dorsal ruffling, and subsequent macropinocytosis. Pharmacological membrane tension manipulation, confocal microscopy, PLD2 inhibition, lipid raft/nanodomain analysis, PA production measurement Journal of Cell Science Medium 31391241
2017 PLD2 mediates phosphorylation of occludin via c-Src kinase and induces its proteasomal degradation, thereby disrupting intestinal epithelial tight junctions; intestinal epithelial-specific Pld2 knockout mice are protected from DSS-induced colitis. Conditional Pld2 knockout mice, Western blot for occludin and c-Src phosphorylation, proteasome inhibitor, pharmacological PLD2 inhibition Scientific Reports High 28484281
2014 PLD2 inhibitors FIPI and NFOT are mixed-kinetics inhibitors: FIPI acts at the S757 HKD2 catalytic site, whereas NFOT binds both the catalytic site (S757/S648) and an allosteric PIP2-binding pocket (R210/R212) in the PH domain. Enzyme kinetics analysis, site-directed mutagenesis, cancer cell invasion assay Biochimica et Biophysica Acta High 25532944
2011 PLD2 interacts with and activates the Fes/Fps tyrosine kinase during myeloid differentiation; PLD2 co-immunoprecipitates with Fes, and PA and PIP2 stimulate Fes activity; PLD2 overexpression shortens the time required for granulocytic differentiation of HL-60 cells. Co-immunoprecipitation, Fes kinase activity assay with PA/PIP2, siRNA, overexpression, differentiation time-course analysis Journal of Biological Chemistry Medium 22094461
2019 PLD2-generated PA directly binds IQGAP1 scaffold protein and promotes its plasma membrane recruitment; this PLD2-PA-IQGAP1 pathway is required for VSMC membrane ruffle formation and migration, and for injury-induced neointimal formation. PLD2 knockout mice (carotid ligation model), PA-IQGAP1 binding assay, IQGAP1 knockdown, PA-binding-deficient IQGAP1 mutant rescue, ruffle and migration assays FASEB Journal High 30811216
2020 PLD1 couples to TLR4/MyD88 signaling for M1 macrophage polarization, while PLD2 couples to IL-4R/JAK3 signaling for M2 macrophage polarization; LPS enhances TLR4-PLD1 interaction and IL-4 induces IL-4R-PLD2 association. Co-immunoprecipitation, PLD isoform-specific knockouts (Pld1-LyzCre, Pld2-LyzCre), cytokine assays, in vivo sepsis and injury models Journal of Cellular Physiology High 33368247
2003 S100B-RAGE interaction triggers activation of PLD2, which mediates ROS production and augments Ang II-induced JAK2 phosphorylation and VSMC proliferation. PLD2 inhibition, overexpression, RAGE-dependent signaling assays, ROS measurement, JAK2 phosphorylation assay Diabetes Medium 12941779
2021 Adipocyte-specific PLD2 deletion augments thermogenesis by improving mitochondrial quality and quantity via p62; PLD2 inhibition confers resistance to diet-induced obesity and insulin resistance. Adipocyte-specific Pld2 knockout mice, PLD2 pharmacological inhibition, mitochondrial quality assays, p62 pathway analysis Journal of Experimental Medicine Medium 34940790
2022 PLD2 deletion protects against LPS-induced tight junction disruption in ALI via the PA/STAT3 axis; PLD2-generated PA increases STAT3 phosphorylation, which degrades endothelial tight junction proteins (claudin-5, occludin, ZO-1). PLD2 knockout mice, exogenous PA treatment, STAT3 inhibition, Western blot, permeability assays International Immunopharmacology Medium 36700766
2007 Mutation of PLD2-Y179F leads to increased AKT phosphorylation (T308 and S473) and DNA synthesis in a PI3K-dependent manner; activated Akt then phosphorylates PLD2 at T175 in a feedback loop; lipase activity (PA synthesis) is required for the DNA synthesis effect. Site-directed mutagenesis, PI3K inhibitor (LY294004), AKT phosphorylation assay, DNA synthesis (BrdU), ERK phosphorylation Cellular Signalling Medium 18006275
2012 The C-terminal domain (residues 578–933) of PLD2 interacts with CKIIβ subunit and promotes its ubiquitin-dependent proteasomal degradation; PLD2 relocates CKIIβ to the plasma membrane, and this function is independent of PLD2 catalytic activity. Co-immunoprecipitation, deletion mutants, overexpression/knockdown, proteasome inhibitor, immunofluorescence BMB Reports Medium 21944249
2025 PLD2 plays a role in retaining mutant KIT in the Golgi/TGN of GIST cells; KIT mut activates PLD2 through the PLCγ2–PKD2 cascade (independently of PI4KIIIβ), and PLD2 activity is required for γ-adaptin association with GGA1, mediating Golgi retention. PLD2 knockdown, PLD inhibitor (CAY10594), co-immunoprecipitation, immunofluorescence bioRxiv (preprint)preprint Medium bio_10.1101_2025.03.02.640696
2025 Oleate enhances PLD2 S-acylation at Cys223 and Cys224, disrupting PLD2 lipid raft localization and increasing its colocalization with PIP2-enriched microdomains; this modulation activates both PLD2 lipase activity and its GEF activity toward Cdc42. Mutation of S-acylation sites abolishes PLD2-mediated Cdc42 activation and filopodia formation. Confocal microscopy, lipid raft isolation, S-acylation assay, site-directed mutagenesis (Cys223/224), GEF activity assay, filopodia quantification Journal of Lipid Research High 41223946

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nature communications 451 24637612
2016 Membrane Tension Acts Through PLD2 and mTORC2 to Limit Actin Network Assembly During Neutrophil Migration. PLoS biology 147 27280401
2000 Interaction of the type Ialpha PIPkinase with phospholipase D: a role for the local generation of phosphatidylinositol 4, 5-bisphosphate in the regulation of PLD2 activity. The EMBO journal 107 11032811
1998 Characterization of human PLD2 and the analysis of PLD isoform splice variants. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 101 9761774
1998 PLD2 complexes with the EGF receptor and undergoes tyrosine phosphorylation at a single site upon agonist stimulation. The Journal of biological chemistry 101 9837959
2004 Structural determinants of PLD2 inhibition by alpha-synuclein. Journal of molecular biology 83 15033366
2006 Phagocyte cell migration is mediated by phospholipases PLD1 and PLD2. Blood 81 16873675
2003 S100B-RAGE-mediated augmentation of angiotensin II-induced activation of JAK2 in vascular smooth muscle cells is dependent on PLD2. Diabetes 80 12941779
2000 Regulation of human PLD1 and PLD2 by calcium and protein kinase C. Biochimica et biophysica acta 59 10838164
2004 Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK. American journal of physiology. Heart and circulatory physiology 54 14704231
2017 Binding of PLD2-Generated Phosphatidic Acid to KIF5B Promotes MT1-MMP Surface Trafficking and Lung Metastasis of Mouse Breast Cancer Cells. Developmental cell 51 29033361
2018 Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2-CD36 functional interdependence. Journal of leukocyte biology 48 29656494
2013 MicroRNA-203 inhibits the proliferation and invasion of U251 glioblastoma cells by directly targeting PLD2. Molecular medicine reports 48 24270883
2006 PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals. Cellular signalling 46 16837165
2011 Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the GTPase Rac2. Proceedings of the National Academy of Sciences of the United States of America 42 22106281
2011 The mechanism of cell membrane ruffling relies on a phospholipase D2 (PLD2), Grb2 and Rac2 association. Cellular signalling 39 21419846
2006 The elucidation of novel SH2 binding sites on PLD2. Oncogene 38 16407827
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 Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin. Scientific reports 33 28484281
2012 Serum deprivation confers the MDA-MB-231 breast cancer line with an EGFR/JAK3/PLD2 system that maximizes cancer cell invasion. Journal of molecular biology 33 23238254
2019 An acute decrease in plasma membrane tension induces macropinocytosis via PLD2 activation. Journal of cell science 32 31391241
2007 The Grb2/PLD2 interaction is essential for lipase activity, intracellular localization and signaling in response to EGF. Journal of molecular biology 32 17276458
2016 Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells. The Journal of biological chemistry 31 27510034
2011 The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (and a surprise discovery: PLD2 is a GEF). Cellular signalling 31 21740967
2008 Cdk5 phosphorylates PLD2 to mediate EGF-dependent insulin secretion. Cellular signalling 30 18625302
2001 Regulation of phospholipase D (PLD) in growth plate chondrocytes by 24R,25-(OH)2D3 is dependent on cell maturation state (resting zone cells) and is specific to the PLD2 isoform. Biochimica et biophysica acta 30 11341968
2011 Cell invasion of highly metastatic MTLn3 cancer cells is dependent on phospholipase D2 (PLD2) and Janus kinase 3 (JAK3). Journal of molecular biology 25 21414324
2011 Evidence for two CRIB domains in phospholipase D2 (PLD2) that the enzyme uses to specifically bind to the small GTPase Rac2. The Journal of biological chemistry 24 21378159
2020 PLD1 and PLD2 differentially regulate the balance of macrophage polarization in inflammation and tissue injury. Journal of cellular physiology 23 33368247
1997 Molecular cloning and chromosome mapping of rat phospholipase D genes, Pld1a, Pld1b and Pld2. Cytogenetics and cell genetics 23 9533024
2014 Two sites of action for PLD2 inhibitors: The enzyme catalytic center and an allosteric, phosphoinositide biding pocket. Biochimica et biophysica acta 22 25532944
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
2024 Essential role of PLD2 in hypoxia-induced stemness and therapy resistance in ovarian tumors. Journal of experimental & clinical cancer research : CR 19 38403587
2022 PLD2 deletion alleviates disruption of tight junctions in sepsis-induced ALI by regulating PA/STAT3 phosphorylation pathway. International immunopharmacology 18 36700766
2013 Coronin 1B regulates S1P-induced human lung endothelial cell chemotaxis: role of PLD2, protein kinase C and Rac1 signal transduction. PloS one 18 23667561
2012 TLR2 stimulates ABCA1 expression via PKC-η and PLD2 pathway. Biochemical and biophysical research communications 18 23261454
2005 ANG II-induced neointimal growth is mediated via cPLA2- and PLD2-activated Akt in balloon-injured rat carotid artery. American journal of physiology. Heart and circulatory physiology 18 16024570
2007 Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner. Cellular signalling 17 18006275
2005 The uncovering of a novel regulatory mechanism for PLD2: formation of a ternary complex with protein tyrosine phosphatase PTP1B and growth factor receptor-bound protein GRB2. Biochemical and biophysical research communications 17 15896299
2016 Blockade of PLD2 Ameliorates Intestinal Mucosal Inflammation of Inflammatory Bowel Disease. Mediators of inflammation 16 27721573
2017 AQP3 small interfering RNA and PLD2 small interfering RNA inhibit the proliferation and promote the apoptosis of squamous cell carcinoma. Molecular medicine reports 14 28656282
2009 PLD2 has both enzymatic and cell proliferation-inducing capabilities, that are differentially regulated by phosphorylation and dephosphorylation. Biochemical and biophysical research communications 14 19715678
2012 Identification of the catalytic site of phospholipase D2 (PLD2) newly described guanine nucleotide exchange factor activity. The Journal of biological chemistry 13 23035122
2019 Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 30811216
2024 PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 11 38630134
2012 Biochemical and cellular implications of a dual lipase-GEF function of phospholipase D2 (PLD2). Journal of leukocyte biology 11 22750546
2006 Human recombinant PLD2 can repress p65 activity of guinea pigs of chronic asthma in vivo. Cellular & molecular immunology 9 17083197
2021 Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice. The Journal of experimental medicine 8 34940790
2020 HIF1α/PLD2 axis linked to glycolysis induces T-cell immunity in oral lichen planus. Biochimica et biophysica acta. General subjects 8 32205175
2011 Phospholipase D2 (PLD2) shortens the time required for myeloid leukemic cell differentiation: mechanism of action. The Journal of biological chemistry 8 22094461
2023 OGD/R-induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation. Cell biochemistry and function 7 37691020
2020 PLD2-PI(4,5)P2 interactions in fluid phase membranes: Structural modeling and molecular dynamics simulations. PloS one 7 32687545
2012 Structure analysis between the SWAP-70 RHO-GEF and the newly described PLD2-GEF. Small GTPases 6 22858691
2024 Decreased Expression of PLD2 Promotes EMT in Colorectal Cancer Invasion and Metastasis. Journal of Cancer 5 38706911
2012 Cloning of PLD2 from baculovirus for studies in inflammatory responses. Methods in molecular biology (Clifton, N.J.) 5 22426721
2024 The molecular mechanism of PLD2-mediated regulation of apoptosis and cell edema in pancreatic cells via the Nrf2/NF-κB pathway. Scientific reports 4 39461986
2013 Analysis of non-synonymous single-nucleotide polymorphisms and population variability of PLD2 gene associated with hypertension. International journal of bioinformatics research and applications 4 23649737
2024 β-Hydroxy-β-methylbutyrate (HMB) leads to phospholipase D2 (PLD2) activation and alters circadian rhythms in myotubes. Food & function 3 38563085
2024 PLD2 deficiency alleviates endothelial glycocalyx degradation in LPS-induced ARDS/ALI. Biochemical and biophysical research communications 3 38703555
2023 Importance of PLD2 in an IL-23 driven psoriasiform dermatitis model and potential link to human psoriasis. The Journal of dermatology 3 37455419
2017 PLD2 regulates microtubule stability and spindle migration in mouse oocytes during meiotic division. PeerJ 3 28533957
2011 The C-terminal domain of PLD2 participates in degradation of protein kinase CKII β subunit in human colorectal carcinoma cells. BMB reports 3 21944249
2020 [Effect of mi-138 targeting PLD2 gene on proliferation and migration of oral cancer cells]. Shanghai kou qiang yi xue = Shanghai journal of stomatology 1 32524116
2025 Jieyu Wuwei Sinisan formula alleviates depression-like behaviors in CUMS mice by regulating synaptic plasticity through PLD2 pathway. Journal of ethnopharmacology 0 41177242
2025 Oleate activates PLD2 lipase and GEF activity by modulating membrane microdomain dynamics via S-acylation. Journal of lipid research 0 41223946
2025 Optimizing functional recovery after acute ischemic stroke through intensity and frequency of rehabilitation: The critical role of HIF-1α/PLD2/mTOR signaling mechanisms. Experimental neurology 0 41308722
2025 Astragaloside IV Alleviates Colorectal Cancer Metastases by Regulating RALY/PLD2 Axis and Inhibiting Tumoral Exosome Biogenesis. Phytotherapy research : PTR 0 41449865
2024 Differential Control of T-Cell Subsets by Recombinant Human PLD2 in a Mouse Model of Allergic Asthma. Immunological investigations 0 39692536