Affinage

PLD2

Phospholipase D2 · UniProt O14939

Length
933 aa
Mass
106.0 kDa
Annotated
2026-06-10
69 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLD2 is a phosphatidylcholine-hydrolyzing enzyme that generates the second messenger phosphatidic acid (PA) at the plasma membrane to drive cytoskeletal remodeling, directed cell migration, membrane trafficking, and mitogenic signaling (PMID:16873675, PMID:22106281, PMID:29033361). Its lipase activity depends on local PtdIns(4,5)P2: PLD2 recruits Type Iα PIPkinase to its membrane location, and the resulting PIP2 is required for catalysis through a defined allosteric PIP2-binding pocket in the PH domain (PMID:11032811, PMID:25532944). Lipase output is gated by a tyrosine-phosphorylation circuit in which the adaptor Grb2 binds PLD2 at Tyr-169/Tyr-179 to potentiate activity and to direct Grb2/PLD2 co-relocalization to perinuclear Golgi-like structures, while site-specific phosphorylation by Cdk5 (Ser-134) and JAK3 (Tyr-415) further controls activation (PMID:16407827, PMID:17276458, PMID:18625302, PMID:21414324). PLD2-generated PA acts as a direct effector ligand: it binds the kinesin-1 heavy chain KIF5B to promote MT1-MMP surface delivery, invadopodia formation, and metastasis, and binds the scaffold IQGAP1 to drive membrane ruffling, vascular smooth muscle migration, and neointimal formation (PMID:29033361, PMID:30811216). Independently of its lipase function, PLD2 is a guanine nucleotide exchange factor for Rac2 (and Cdc42), using a catalytic site built from hydrophobic PX-domain residues with the PH domain providing CRIB-mediated auxiliary docking, thereby driving actin polymerization, chemotaxis, and phagocytosis (PMID:22106281, PMID:21378159, PMID:23035122, PMID:41223946). PLD2 also serves as a membrane-tension mechanosensor that, together with mTORC2, limits actin nucleation during neutrophil migration, and couples to ARF6 and RalA to control intraluminal-vesicle/exosome biogenesis and caveolae-mediated endocytosis (PMID:27280401, PMID:24637612, PMID:27510034). Through a TOS-like motif PLD2 forms a raptor-containing mTOR complex required for mitogen-induced S6K1/4EBP1 phosphorylation, linking it to growth control (PMID:16837165). In vivo, PLD2 governs epithelial and endothelial barrier integrity via degradation of tight-junction proteins, M2 macrophage polarization through IL-4R/JAK3, and adipocyte thermogenesis via p62-dependent mitochondrial quality control (PMID:28484281, PMID:33368247, PMID:34940790).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1998 High

    Established that PLD2 is physically and functionally coupled to receptor tyrosine kinase signaling, defining a phosphoregulatory input to its activity.

    Evidence Co-IP and Tyr-11 mutagenesis with in vivo PLD activity assay in HEK293 cells

    PMID:9837959

    Open questions at the time
    • Did not establish the downstream consequence of EGFR coupling for a cellular process
    • Kinase directly phosphorylating Tyr-11 not resolved here
  2. 2000 High

    Showed PLD2 catalysis requires locally generated PtdIns(4,5)P2, defining a lipid cofactor dependence linked to a recruited PIPkinase.

    Evidence Co-IP, co-transfection and in vivo PLD activity assay with Type Iα PIPkinase

    PMID:11032811

    Open questions at the time
    • Structural basis of PIP2 recognition not defined at this stage
    • Whether PIPkinase recruitment is constitutive or stimulus-dependent unresolved
  3. 2003 Medium

    Placed PLD2 within RAGE-driven oxidative signaling in vascular smooth muscle, broadening its role beyond growth-factor inputs.

    Evidence Pharmacological PLD inhibition and dominant-negative constructs in VSMCs

    PMID:12941779

    Open questions at the time
    • Pharmacological inhibition does not isolate PLD2 from PLD1
    • Direct molecular link from RAGE to PLD2 not mapped
  4. 2004 High

    Identified alpha-synuclein as a structural inhibitor of PLD2 and mapped the inhibitory determinants, providing a regulatory and disease-relevant antagonist.

    Evidence In vitro PLD2 activity assay with recombinant alpha-synuclein deletion/point/phosphomimetic mutants

    PMID:15033366

    Open questions at the time
    • In vivo significance of alpha-synuclein inhibition not demonstrated
    • Whether endogenous alpha-synuclein controls PLD2 in neurons untested here
  5. 2006 High

    Defined the Grb2 interaction surface (Tyr-169/Tyr-179) and resolved how distinct tyrosines partition PLD2 between catalytic and mitogenic (Ras/Sos) outputs.

    Evidence Mutagenesis, GST pulldown, Co-IP and Ras/ERK/DNA-synthesis assays

    PMID:15896299 PMID:16407827

    Open questions at the time
    • Kinase generating the relevant phosphotyrosines not fully defined
    • Stoichiometry within the PTP1B/Grb2/PLD2 ternary complex unresolved
  6. 2006 High

    Demonstrated PLD2 is a raptor-binding component required for mTOR-dependent S6K1/4EBP1 signaling, linking it to translational/growth control via both raptor binding and lipase activity.

    Evidence siRNA knockdown, TOS-motif mutagenesis, Co-IP and rescue with phosphorylation readouts

    PMID:16837165

    Open questions at the time
    • Whether PA is the proximate mTOR-activating signal not directly shown
    • Isoform specificity established only against PLD1
  7. 2006 High

    Established PLD2 lipase activity as essential for chemokine-directed chemotaxis, tying PA generation to migratory cell behavior.

    Evidence siRNA, lipase-dead mutants, PLD activity and migration assays in HL-60 cells

    PMID:16873675

    Open questions at the time
    • Direct PA effectors driving migration not identified at this stage
    • Relative contributions of PLD1 vs PLD2 across chemokines incompletely separated
  8. 2007 High

    Showed Grb2 is required for cellular PLD2 activity and for EGF-driven Golgi relocalization, integrating adaptor binding with subcellular targeting.

    Evidence shRNA silencing with SH2-mutant rescue, Co-IP and immunofluorescence

    PMID:17276458 PMID:18006275

    Open questions at the time
    • Functional consequence of Golgi-localized PLD2 not defined
    • Feedback from Akt (Thr-175) on PLD2 output not mechanistically resolved
  9. 2008 High

    Identified Cdk5-mediated Ser-134 phosphorylation as a required activating event for EGF-dependent PLD2 activation and insulin secretion.

    Evidence In vitro kinase assay, S134A mutagenesis and insulin secretion assays in beta-cells

    PMID:18625302

    Open questions at the time
    • How Ser-134 phosphorylation alters catalysis mechanistically unresolved
    • Interplay with tyrosine-phosphorylation circuit not tested
  10. 2009 Medium

    Resolved a phosphorylation switch in which Grb2-bound phospho-PLD2 favors lipase activity while CD45-dependent dephosphorylation drives proliferation.

    Evidence In vitro assays with purified proteins, CD45 siRNA and phospho-deficient mutants

    PMID:19715678

    Open questions at the time
    • Mechanism by which dephosphorylated PLD2 drives proliferation not defined
    • Physiological CD45 relevance outside the assay system unclear
  11. 2011 High

    Established the lipase-independent GEF function of PLD2 toward Rac2, redefining PLD2 as a bifunctional enzyme driving actin-dependent processes.

    Evidence In vitro GEF assays with recombinant proteins, FRET, Kd measurement, mutagenesis and functional assays

    PMID:21378159 PMID:21419846 PMID:22106281

    Open questions at the time
    • How lipase and GEF activities are coordinated in time/space partially open
    • Negative-feedback inhibition by Rac2-GTP characterized only in vitro
  12. 2011 Medium

    Extended PLD2 partner repertoire to oncogenic kinase Fes/Fps and JAK3, linking PLD2 to leukemic differentiation and cancer cell invasion via Tyr-415.

    Evidence Co-IP with domain mutants, kinase/PLD activity assays, siRNA and invasion assays

    PMID:21414324 PMID:22094461

    Open questions at the time
    • Direct PA effectors in invasion not identified at this stage
    • STAT-independence of JAK3-PLD2 axis shown but mechanism incompletely defined
  13. 2012 High

    Mapped the PX-domain catalytic residues sufficient for GEF activity and a separable PH-domain docking site, mechanistically dissociating GEF from lipase function.

    Evidence GST-fusion GEF assays with point mutants and chemotaxis/phagocytosis assays

    PMID:23035122

    Open questions at the time
    • Structural model of the GEF active site not solved
    • How PX-GEF and HKD-lipase domains influence each other unresolved
  14. 2012 Medium

    Showed PLD2 promotes proteasomal degradation of CKIIβ via its C-terminal domain independently of lipase activity, indicating a scaffolding/adaptor role.

    Evidence Co-IP domain mapping, ubiquitination and proteasome-inhibitor assays in HCT116

    PMID:21944249

    Open questions at the time
    • E3 ligase mediating CKIIβ degradation not identified
    • Physiological significance of CKIIβ regulation untested in vivo
  15. 2014 High

    Connected PLD2 to ARF6- and RalA-controlled membrane trafficking, defining roles in exosome biogenesis and caveolae-mediated endocytosis.

    Evidence Co-IP, siRNA, EM, PA biosensor imaging and TIRF/uptake assays

    PMID:24637612 PMID:27510034

    Open questions at the time
    • Direct PA effectors at MVB and caveolae steps not fully enumerated
    • How ARF6 versus RalA inputs are coordinated unresolved
  16. 2014 High

    Defined catalytic (Ser-757/Ser-648) and allosteric PIP2-binding (Arg-210/Arg-212) sites through inhibitor pharmacology, providing the structural logic of PLD2 regulation and druggability.

    Evidence Enzyme kinetics with FIPI/NFOT, site-directed mutagenesis and invasion assays

    PMID:25532944

    Open questions at the time
    • Full atomic structure of PLD2 not determined
    • Allosteric coupling between PIP2 pocket and catalysis not structurally visualized
  17. 2016 High

    Established PLD2 as a membrane-tension mechanosensor acting through mTORC2 to limit actin nucleation, embedding it in a migratory feedback loop.

    Evidence Genetic KO neutrophils, membrane tension measurement, actin/chemotaxis assays and modeling

    PMID:27280401

    Open questions at the time
    • How membrane tension is transduced into PLD2 activation not molecularly defined
    • Relationship to its GEF versus lipase activity in this context unclear
  18. 2017 High

    Identified PA-binding effectors KIF5B and the c-Src/occludin axis, mechanistically linking PLD2-generated PA to MT1-MMP trafficking, metastasis, and barrier control.

    Evidence Liposome pulldown, in vitro PA-binding, KO mouse models, biotinylation and colitis/DSS assays

    PMID:28484281 PMID:29033361

    Open questions at the time
    • Selectivity of PA recognition among KIF5B and other effectors not fully mapped
    • Whether occludin phosphorylation is direct or PA-effector-mediated unresolved
  19. 2018 High

    Defined an isoform-specific PLD2 requirement coupling CD36-dependent oxLDL phagocytosis to WASP/Grb2/actin assembly in macrophages.

    Evidence PLD-null BMDMs, selective inhibitor, Co-IP and phagocytosis assays

    PMID:29656494

    Open questions at the time
    • Whether PLD2 lipase or GEF activity drives this complex not separated
    • Direct PLD2-CD36 contact versus indirect coupling unresolved
  20. 2019 High

    Extended the PA-effector model to IQGAP1 in vascular remodeling and established a tension-driven PLD2 pathway for ruffling and macropinocytosis.

    Evidence In vitro PA-IQGAP1 binding, KO mice, carotid ligation, PA biosensor and macropinocytosis assays

    PMID:30811216 PMID:31391241

    Open questions at the time
    • How tension-induced nanodomain disintegration activates PLD2 mechanistically open
    • PA-effector hierarchy at the ruffle not fully defined
  21. 2020 High

    Established isoform-segregated receptor coupling whereby PLD2 selectively partners IL-4R/JAK3 to drive M2 macrophage polarization.

    Evidence Reciprocal Co-IP, PLD1/PLD2 KO mice and in vivo inflammation models

    PMID:33368247

    Open questions at the time
    • Downstream PA targets in M2 programming not identified
    • Whether PLD2 catalytic or GEF activity drives polarization untested
  22. 2021 High

    Defined a metabolic role for PLD2 in adipocyte thermogenesis through p62-dependent mitochondrial quality control, with whole-body metabolic consequences.

    Evidence Adipocyte-specific KO mice, HFD model, selective inhibitor and mitochondrial/p62 analyses

    PMID:34940790

    Open questions at the time
    • Molecular link from PLD2 to p62 not defined
    • Whether PA directly modulates mitochondrial quality control unresolved
  23. 2024 Medium

    Placed PLD2 in a HIF-1α-driven transcriptional-epigenetic axis promoting cancer stemness and chemoresistance.

    Evidence ATAC-seq, HRE reporter, CRISPR/siRNA, xenografts and reprogramming assays in ovarian cancer

    PMID:38403587

    Open questions at the time
    • How PLD2 activity alters AP-1-bound chromatin accessibility mechanistically unclear
    • Whether lipase product PA is required for the chromatin effect untested
  24. 2025 Medium

    Expanded PLD2 GEF function to Cdc42 and showed S-acylation at Cys-223/Cys-224 controls lipid-raft partitioning and GEF output, adding a lipid-modification layer of regulation.

    Evidence S-acylation and Cdc42 GEF assays, Cys mutagenesis, raft isolation and filopodia imaging

    PMID:41223946

    Open questions at the time
    • Enzyme mediating PLD2 S-acylation not identified
    • How raft partitioning mechanistically toggles GEF specificity unresolved
  25. 2025 Medium

    Positioned PLD2 downstream of PLCγ2-PKD2 in oncogenic KIT signaling to retain mutant KIT at the Golgi/TGN via GGA1/γ-adaptin trafficking.

    Evidence PLD inhibitor, siRNA, Co-IP of GGA1/γ-adaptin and KIT localization assays in GIST cells (preprint)

    PMID:bio_10.1101_2025.03.02.640696

    Open questions at the time
    • Preprint not peer-reviewed
    • Whether PA directly recruits the GGA1/γ-adaptin machinery not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PLD2's two enzymatic activities (PA-generating lipase and Rac2/Cdc42 GEF), its scaffolding functions, and its multiple post-translational and lipid modifications are coordinated in space and time to select among migration, trafficking, metabolic, and transcriptional outputs remains unresolved.
  • No integrated structural model coupling lipase, GEF, and scaffolding domains
  • Determinants of context-specific output selection unknown
  • PA effector hierarchy across cell types incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0008289 lipid binding 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 1
Partners
ARF6EGFRGRB2IQGAP1JAK3KIF5BRAC2RALA
Complex memberships
PLD2/Grb2/PTP1B ternary complexmTOR/raptor complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PLD2 associates with the EGF receptor in a ligand-independent manner and undergoes tyrosine phosphorylation at Tyr-11 upon EGF receptor activation; mutation of Tyr-11 to phenylalanine enhanced basal PLD2 activity approximately 2-fold but did not alter EGF-mediated increase. Co-immunoprecipitation, site-directed mutagenesis, in vivo PLD activity assay in transiently transfected HEK293 cells The Journal of biological chemistry High 9837959
2000 PLD2 interacts with Type Iα PIPkinase (PI4P 5-kinase α) and recruits it to its intracellular location; PLD2 activity in vivo can be regulated solely by the expression of this lipid kinase, establishing that PtdIns(4,5)P2 generated locally by the PIPkinase is required for PLD2 activity. Co-immunoprecipitation, co-transfection, in vivo PLD activity assay The EMBO journal High 11032811
2000 PLD1 and PLD2 are both 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 by immunoprecipitation; PLD2 (but not PLD1) activity is also enhanced by co-expression with PKCδ in the presence of calcium ionophore. Sf9 cell expression system, in vivo PtdEth assay, immunoprecipitation, membrane reconstitution assay Biochimica et biophysica acta Medium 10838164
2003 S100B-RAGE interaction triggers activation of PLD2, leading to ROS production and augmentation of Ang II-induced JAK2 tyrosine phosphorylation and VSMC proliferation; PLD2 is positioned between RAGE signaling and ROS/JAK2 activation in this pathway. Pharmacological inhibition of PLD, siRNA/dominant-negative constructs, cell proliferation and signaling assays in VSMCs Diabetes Medium 12941779
2004 Alpha-synuclein inhibits PLD2 in vitro; PLD2 inhibition requires a lipid-stabilized alpha-helical structure in exon 4 (residues 56-102) and C-terminal residues 130-140 (exon 6) of alpha-synuclein; phosphorylation at Ser129, Tyr125, or Tyr136 of alpha-synuclein abolishes PLD2 inhibition; A53T mutant is a more potent PLD2 inhibitor than WT. In vitro PLD2 activity assay with recombinant proteins, deletion and point mutants of alpha-synuclein, phosphomimetic mutations Journal of molecular biology High 15033366
2004 VEGFR-2 and PLD2 are co-localized in caveolae-enriched fractions of endothelial cells; VEGF stimulates PLD activity via VEGFR-2/PKC-δ; PLD-generated phosphatidic acid mediates VEGF-induced MEK/ERK phosphorylation and cellular proliferation; intact caveolae are required for this signaling cascade. Membrane fractionation, 1-butanol inhibition, exogenous PA rescue, pharmacological inhibitor panel, cholesterol depletion with MβCD American journal of physiology. Heart and circulatory physiology Medium 14704231
2005 PLD2 exists in a ternary complex with protein tyrosine phosphatase PTP1B and the adaptor protein Grb2; PTP1B treatment of PLD2 immunoprecipitates paradoxically increases both lipase activity and tyrosine phosphorylation; Grb2 addition to cell extracts elevates PLD2 tyrosine phosphorylation >10-fold. Co-immunoprecipitation, immunoblotting, in vitro phosphatase treatment, lipase activity assay Biochemical and biophysical research communications Medium 15896299
2006 PLD2 activity is essential for chemotaxis of HL-60 cells toward FMLP and IL-8 (via CXCR-1), while ENA-78 (CXCR-2) selectively activates endogenous PLD2; a lipase-inactive PLD1-K830R mutant negates chemotactic responses; both PLD isoforms associate with cell polarity markers and F-actin polymerization in response to IL-8. siRNA knockdown, overexpression of WT and lipase-inactive mutants, in vitro PLD activity assay, cell migration assay (chemokinesis/chemotaxis), immunofluorescence microscopy Blood High 16873675
2006 PLD2 forms a functional complex with mTOR/raptor via a TOS-like motif (Phe-Glu-Val-Gln-Val, residues 265-269) in PLD2; siRNA-mediated knockdown of PLD2 (but not PLD1) profoundly reduces mitogen-induced phosphorylation of S6K1 and 4EBP1; PLD2-dependent mTOR activation requires both raptor binding and lipase activity, as raptor-binding-deficient or lipase-inactive PLD2 cannot restore mTOR activation. siRNA knockdown, co-immunoprecipitation, mutagenesis of TOS motif, in vivo S6K1/4EBP1 phosphorylation assay, rescue experiments Cellular signalling High 16837165
2006 PLD2 contains two SH2-binding sites at Tyr-169 and Tyr-179 that mediate interaction with the SH2 domain of Grb2; Tyr-169 modulates enzymatic activity while Tyr-179 regulates total tyrosine phosphorylation; Grb2 binds PLD2 independently of lipase activity; PLD2-Y179F (but not WT) causes increased Ras activity, ERK phosphorylation and DNA synthesis, mediated through Sos recruitment. Deletion and point mutagenesis, GST pulldown, co-immunoprecipitation, in vitro PLD activity assay, ERK/Ras activation assays, DNA synthesis assay Oncogene High 16407827
2007 Grb2 is essential for PLD2 activity in vivo; shRNA silencing of Grb2 reduces PLD2 activity and is rescued only by SH2-competent Grb2; Grb2 and PLD2 re-localize to perinuclear Golgi-like structures after EGF stimulation in a manner dependent on PLD2 residues Y169/Y179 and the Grb2 SH2 domain. shRNA-mediated Grb2 silencing, rescue with SH2-deficient mutant, co-immunoprecipitation, immunofluorescence microscopy, in vitro PLD activity assay Journal of molecular biology High 17276458
2007 PLD2-Y179F mutation (unavailability of Y179 for phosphorylation) leads to increased basal Akt phosphorylation at T308 and S473, enhanced DNA synthesis, ERK phosphorylation, and G0/G1 transition markers in a PI3K-dependent manner; active Akt in turn phosphorylates PLD2 at Thr-175; lipase-inactive double mutant Y179F-K758R abolishes the DNA synthesis effect, indicating PLD2 enzymatic activity is required. Site-directed mutagenesis, transfection in COS7 cells, Akt/ERK phosphorylation Western blot, PI3K inhibitor (LY294002), DNA synthesis assay Cellular signalling Medium 18006275
2008 Cyclin-dependent kinase 5 (Cdk5) phosphorylates PLD2 at Ser-134 in vitro and in cells; this phosphorylation is critical for EGF-dependent PLD2 activation and insulin secretion; PLD2-S134A mutant fails to show EGF-dependent phosphorylation, activation, or insulin secretion in pancreatic beta-cell lines. In vitro kinase assay, Cdk5 inhibitor (roscovitine), dominant-negative Cdk5, site-directed mutagenesis (S134A), co-immunoprecipitation, insulin secretion assay Cellular signalling High 18625302
2009 Phosphorylated PLD2 (aided by Grb2) mediates lipase activity, whereas dephosphorylated PLD2 (dependent on phosphatase CD45) mediates induction of cell proliferation; Y179F and Y511F mutations both enhance DNA synthesis through a CD45-dependent mechanism; purified PLD2 is activated by Grb2 and deactivated by CD45 in vitro. In vitro activity assay with purified proteins, siRNA knockdown of CD45, phosphorylation-deficient mutants (Y179F, Y511F), proliferation markers (PCNA, p27KIP1, phospho-histone H3) Biochemical and biophysical research communications Medium 19715678
2011 PLD2 directly binds the small GTPase Rac2 and functions as a guanine nucleotide exchange factor (GEF), switching Rac2 from GDP-bound to GTP-bound state; GEF activity is demonstrable in vitro with recombinant proteins without lipid substrates; a catalytically inactive lipase mutant (PLD2-K758R) retains GEF activity; PLD2 PH domain residues 263-266 (CRIB region) and PX domain mediate Rac2 binding; Rac2 Switch-1 residue N17 is required for PLD2 binding; PLD2-initiated Rac2 activation enhances cell adhesion, chemotaxis, and phagocytosis. In vitro GEF assay with recombinant proteins, GDP dissociation and GTP association kinetics, co-immunoprecipitation, mutagenesis, cell functional assays (adhesion, chemotaxis, phagocytosis), siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 22106281
2011 PLD2 contains two CRIB motifs (CRIB-1 and CRIB-2) in and around the PH domain that mediate specific binding to Rac2; binding is saturable with apparent Kd ~3 nM; PLD2 binds more efficiently to Rac2-GTP than Rac2-GDP; increasing Rac2-GTP concentrations inhibit PLD2 lipase activity, creating a negative feedback termination signal. Co-immunoprecipitation, FRET with CFP-Rac2/YFP-PLD2 in living cells, in vitro binding with affinity-purified recombinant proteins, deletion mutants (ΔCRIB-1/2), lipase activity assay The Journal of biological chemistry High 21378159
2011 PLD2 co-localizes with Grb2 at actin-rich membrane protrusions; PLD2-Y169 interacts with the SH2 domain of Grb2 (confirmed by immunoprecipitation); Grb2 binding enhances PLD2 activity; Rac2 is a third required component for full actin polymerization and membrane ruffle formation in vivo; PLD2 Y169F or Grb2 R86K mutations negate this effect. YFP/CFP fluorescent chimeras, co-immunoprecipitation, Western blot, in vitro PLD activity assay, cell ruffling assay with M-CSF stimulation Cellular signalling High 21419846
2011 PLD2 interacts with and activates the oncogenic tyrosine kinase Fes/Fps; PLD2 overexpression elevates Fes activity in a manner dependent on phosphatidic acid and PIP2; Co-immunoprecipitation demonstrates PLD2-Fes physical interaction requiring Fes SH2 domain (R483K mutant negates interaction); this PLD2/Fes axis shortens time required for myeloid leukemic cell differentiation. Co-immunoprecipitation, Fes kinase activity assay, overexpression and siRNA knockdown, cell differentiation assay The Journal of biological chemistry Medium 22094461
2011 JAK3 phosphorylates PLD2 at Tyr-415, enabling PLD2 activation; JAK3 knockdown abrogates PLD2 lipase activity and EGF-stimulated cancer cell invasion; JAK3 activation of PLD2 for invasion operates independently of the canonical STAT pathway. siRNA knockdown of JAK3, site-directed mutagenesis (Y415), in vitro PLD activity assay, Matrigel invasion assay Journal of molecular biology Medium 21414324
2012 The PX domain of PLD2 is sufficient for GEF activity toward Rac2; the GEF catalytic site is formed by hydrophobic residues Phe-107, Phe-129, Leu-166, and Leu-173 plus Arg-172 in the PX domain; mutations at these residues abolish GEF activity without affecting Rac2 binding; the PH domain (Ile-306 to Ala-310) provides an auxiliary docking site for Rac2 during catalysis; PX/PH mutants abolish chemotaxis and phagocytosis. GST fusion protein GEF assay, purified recombinant protein assay, site-directed mutagenesis, cell functional assays (chemotaxis, phagocytosis) The Journal of biological chemistry High 23035122
2012 Serum-deprived MDA-MB-231 breast cancer cells upregulate an EGFR/JAK3/PLD2-PA system; both EGFR and JAK3 directly regulate PLD2 activity to mediate cell invasion; combined inhibition of JAK3 and PLD2 is especially effective in serum-deprived cells. Flavonoid kinase inhibitor (apigenin), RNA silencing, in vitro PLD activity assay, Matrigel invasion assay Journal of molecular biology Medium 23238254
2014 ARF6 and its effector PLD2 regulate syntenin exosome biogenesis by controlling budding of intraluminal vesicles (ILVs) into multivesicular bodies (MVBs); ARF6 also controls EGFR degradation through degradative MVBs but does not affect HIV-1 budding, excluding general ESCRT effects. Co-immunoprecipitation, siRNA knockdown, electron microscopy, nanoparticle tracking, functional exosome assays Nature communications High 24637612
2014 PLD2 inhibitor FIPI acts at the catalytic site (Ser-757 in HKD2) with mixed-kinetics; PLD2-specific inhibitor NFOT acts at two sites: the catalytic site (Ser-757/Ser-648) and an allosteric PIP2-binding site (Arg-210/Arg-212) in a hydrophobic pocket (Phe-244/Leu-245/Leu-246) in the PH domain; NFOT prevents cancer cell invasion, and this is lost in cells overexpressing PLD2-F244A/L245A/L246A or PLD2-R210A/R212A or PLD2-S757/S648 mutants. Enzyme kinetics, site-directed mutagenesis, mixed-inhibition kinetics analysis, cancer cell invasion assay Biochimica et biophysica acta High 25532944
2016 Elevated membrane tension acts through PLD2 and mTORC2 to limit actin nucleation and cell protrusion; in the absence of PLD2, neutrophils exhibit larger leading edges, higher membrane tension, and defective chemotaxis; this biochemical feedback loop (via PLD2 and mTORC2) is distinct from direct mechanical inhibition of actin assembly. PLD2 knockout (genetic), membrane tension measurement, actin dynamics assay, chemotaxis assay, mathematical modeling PLoS biology High 27280401
2016 RalA activates PLD2 in endothelial cells; PLD2-generated phosphatidic acid (PA) facilitates caveolae-mediated endocytosis and trafficking; PA co-localizes with caveolin-1 upon albumin stimulation; dominant-negative PLD2 blocks PA accumulation at caveolae and inhibits caveolae fusion. siRNA knockdown of RalA and PLD2, co-immunoprecipitation, PA biosensor (GFP-PASS), TIRF microscopy of Cav-1-RFP, fluorescent BSA uptake assay The Journal of biological chemistry High 27510034
2017 PLD2-generated PA specifically and directly binds to the C-terminus of KIF5B (kinesin-1 heavy chain), identified by liposome pulldown screen; PA binding is required for vesicular association of KIF5B, surface localization of MT1-MMP, invadopodia formation, and cancer cell invasion; PLD2 knockout inhibits lung metastases in MMTV-Neu transgenic mice. Liposome pulldown screen, in vitro PA-KIF5B binding assay, PLD2 knockout mouse model, surface biotinylation, invasion assay, lung metastasis quantification Developmental cell High 29033361
2017 PLD2 mediates phosphorylation of occludin and induces its proteasomal degradation via a c-Src kinase-dependent pathway; intestinal-epithelial-cell-specific Pld2 knockout mice are protected from DSS-induced colitis; DSS induces PLD2 expression which downregulates occludin in colon epithelial cells. Intestinal-specific Pld2 knockout mice, DSS colitis model, Western blot for occludin phosphorylation and degradation, proteasome inhibitor experiments, c-Src inhibitor Scientific reports High 28484281
2018 PLD2 (but not PLD1)-null macrophages cannot fully phagocytose aggregated oxidized LDL; PLD2 couples Agg-oxLDL phagocytosis with WASP, Grb2, and actin; CD36 and PLD2 exhibit mutual dependence: without PLD2, CD36 cannot engage in Agg-oxLDL removal; without CD36, PLD2 cannot form protein complexes with WASP or actin. Bone marrow-derived macrophages from PLD-null mice, PLD2-selective inhibitor, co-immunoprecipitation, phagocytosis assay, CD36 blocking antibody Journal of leukocyte biology High 29656494
2019 PLD2-generated PA specifically binds IQGAP1 scaffold protein; PA-IQGAP1 binding is required for plasma membrane recruitment of IQGAP1; similar to PLD2 inhibition, IQGAP1 knockdown blocks membrane ruffle formation and VSMC migration, which is rescued by WT IQGAP1 but not PA-binding-deficient IQGAP1 mutant; PLD2 deficiency reduces neointimal formation in carotid artery ligation model. In vitro PA-IQGAP1 binding assay, PLD2 knockout mice, carotid artery ligation model, siRNA knockdown, membrane fractionation, cell migration assay FASEB journal High 30811216
2019 An acute decrease in plasma membrane tension activates PLD2 by causing nanodomain disintegration; PLD2 activation generates PA leading to PI(4,5)P2-enriched dorsal membrane ruffling and macropinocytosis; this pathway is prominent in myotubes and represents a PM tension homeostasis mechanism. Plasma membrane tension manipulation, PLD2 inhibitor, PA biosensor, F-actin/PI(4,5)P2 imaging, macropinocytosis assay, siRNA knockdown Journal of cell science Medium 31391241
2020 PLD1 selectively couples to TLR4/MyD88 to regulate M1 macrophage polarization, while PLD2 selectively couples to IL-4 receptor/JAK3 to regulate M2 macrophage polarization; LPS enhances TLR4/MyD88 interaction with PLD1; IL-4 induces IL-4R/JAK3 association with PLD2; PLD2 ablation intensifies M1-predominant disease severity. Co-immunoprecipitation showing isoform-specific receptor associations, PLD1/PLD2 knockout mice, macrophage polarization assays, in vivo sepsis and injury models Journal of cellular physiology High 33368247
2021 PLD2 deletion in adipose tissue or pharmacological PLD2 inhibition augments adaptive thermogenesis via p62-mediated improvement in mitochondrial quality and quantity in adipocytes; adipocyte-specific Pld2 knockout mice are resistant to high-fat diet-induced obesity, glucose intolerance, and insulin resistance. Adipocyte-specific Pld2 knockout mice, high-fat diet model, PLD2-specific inhibitor, mitochondrial biogenesis assays, p62 pathway analysis The Journal of experimental medicine High 34940790
2022 PLD2-generated PA increases STAT3 phosphorylation; activated STAT3 mediates PA-induced degradation of endothelial tight junction proteins (claudin-5, occludin, ZO-1) in LPS-induced ALI; PLD2 knockout reduces PA production, STAT3 phosphorylation, and TJ protein degradation. PLD2 knockout mice, LPS-induced ALI model, HUVEC in vitro model, exogenous PA treatment, STAT3 inhibitor, Western blot, ELISA for PA International immunopharmacology Medium 36700766
2024 HIF-1α activates PLD2 transcription through hypoxia response elements; PLD2 overexpression increases chromatin accessibility around stemness genes at AP-1 bound sites (detected by ATAC-seq), leading to upregulation of SOX2, SOX9, and NOTCH1 and promoting cancer stem cell formation and chemoresistance in ovarian cancer. ATAC-seq, ChIP/hypoxia response element reporter, CRISPR/siRNA, xenograft models, iPSC reprogramming assay, in vitro and in vivo pharmacological inhibition Journal of experimental & clinical cancer research Medium 38403587
2025 Oleate (OA) enhances PLD2 S-acylation at Cys-223 and Cys-224, disrupting its lipid raft localization and increasing its colocalization with PIP2-enriched microdomains; PLD2 acts as a GEF for Cdc42 (in addition to Rac2); OA-dependent S-acylation and lipid raft dynamics regulate PLD2's GEF activity toward Cdc42; mutation of S-acylation sites or disruption of lipid rafts abolishes PLD2-mediated Cdc42 activation and filopodia-like protrusion formation. Confocal microscopy, lipid raft isolation, S-acylation assay, Cdc42 GEF activity assay, site-directed mutagenesis of Cys223/Cys224, methyl-β-cyclodextrin lipid raft disruption, filopodia quantification Journal of lipid research Medium 41223946
2025 PLD2 is downstream of the PLCγ2-PKD2 pathway activated by constitutively active KIT mutant in GIST cells; PKD2 activates PLD2 (but not PI4KIIIβ) for Golgi/TGN retention of KIT mutant; PLD2 activity is required for association of γ-adaptin with GGA1 at the Golgi/TGN; knockdown of PLD2 releases KIT mutant from Golgi for lysosomal degradation. PLD inhibitor (CAY10594), siRNA knockdown of PLD2, immunofluorescence microscopy, co-immunoprecipitation of GGA1/γ-adaptin, Western blot for KIT localization and degradation bioRxivpreprint Medium bio_10.1101_2025.03.02.640696
2012 PLD2's C-terminal domain (residues 578-933) interacts with the N-terminal domain of CKIIβ subunit in HCT116 cells; PLD2 overexpression relocates CKIIβ to the plasma membrane and promotes its ubiquitin-dependent proteasomal degradation; the C-terminal domain of PLD2 is sufficient for CKIIβ degradation and lipase activity is not required. Co-immunoprecipitation with domain deletion mutants, subcellular fractionation/immunofluorescence, proteasome inhibitor, ubiquitination assay, siRNA knockdown BMB reports Medium 21944249

Source papers

Stage 0 corpus · 69 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 456 24637612
2016 Membrane Tension Acts Through PLD2 and mTORC2 to Limit Actin Network Assembly During Neutrophil Migration. PLoS biology 151 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 60 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 52 29033361
2018 Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2-CD36 functional interdependence. Journal of leukocyte biology 49 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
2024 Essential role of PLD2 in hypoxia-induced stemness and therapy resistance in ovarian tumors. Journal of experimental & clinical cancer research : CR 20 38403587
2022 PLD2 deletion alleviates disruption of tight junctions in sepsis-induced ALI by regulating PA/STAT3 phosphorylation pathway. International immunopharmacology 20 36700766
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
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
2016 Blockade of PLD2 Ameliorates Intestinal Mucosal Inflammation of Inflammatory Bowel Disease. Mediators of inflammation 17 27721573
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
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
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.] 12 38630134
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
2012 Biochemical and cellular implications of a dual lipase-GEF function of phospholipase D2 (PLD2). Journal of leukocyte biology 11 22750546
2020 HIF1α/PLD2 axis linked to glycolysis induces T-cell immunity in oral lichen planus. Biochimica et biophysica acta. General subjects 9 32205175
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 PLD2-PI(4,5)P2 interactions in fluid phase membranes: Structural modeling and molecular dynamics simulations. PloS one 8 32687545
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
2012 Structure analysis between the SWAP-70 RHO-GEF and the newly described PLD2-GEF. Small GTPases 6 22858691
2024 β-Hydroxy-β-methylbutyrate (HMB) leads to phospholipase D2 (PLD2) activation and alters circadian rhythms in myotubes. Food & function 5 38563085
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 PLD2 deficiency alleviates endothelial glycocalyx degradation in LPS-induced ARDS/ALI. Biochemical and biophysical research communications 4 38703555
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
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
2025 Astragaloside IV Alleviates Colorectal Cancer Metastases by Regulating RALY/PLD2 Axis and Inhibiting Tumoral Exosome Biogenesis. Phytotherapy research : PTR 2 41449865
2025 Jieyu Wuwei Sinisan formula alleviates depression-like behaviors in CUMS mice by regulating synaptic plasticity through PLD2 pathway. Journal of ethnopharmacology 1 41177242
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 1 41308722
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
2026 PLD1 and PLD2 promote an immunosuppressive tumor microenvironment via CCL19-dependent macrophage polarization and PD-L1 induction. Experimental & molecular medicine 0 42243532
2025 Oleate activates PLD2 lipase and GEF activity by modulating membrane microdomain dynamics via S-acylation. Journal of lipid research 0 41223946
2024 Differential Control of T-Cell Subsets by Recombinant Human PLD2 in a Mouse Model of Allergic Asthma. Immunological investigations 0 39692536

Missed literature

Know a paper Affinage missed for PLD2? Flag it for the maintainers and the community.

No submissions yet.