Affinage

LPAR2

Lysophosphatidic acid receptor 2 · UniProt Q9HBW0

Length
348 aa
Mass
38.7 kDa
Annotated
2026-04-28
92 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LPAR2 (LPA2/EDG4) is a lysophosphatidic acid receptor that couples to Gαi, Gαq, and Gα12/13 to activate PLC-β/Ca²⁺, PI3K-Akt, ERK1/2, RhoA, NF-κB, and Wnt/β-catenin signaling, thereby regulating cell survival, proliferation, migration, cytoskeletal dynamics, and epithelial/endothelial barrier integrity (PMID:11040035, PMID:12215548, PMID:25002680, PMID:32654268, PMID:38026263). Signaling specificity is determined by a C-terminal PDZ-binding motif that recruits context-dependent scaffolding partners — NHERF2 promotes Gαq/PLC-β3 coupling and ERK activation, MAGI-3 redirects coupling toward Gα12 to oppose NHERF2-driven responses, and TRIP6 activates TRAF6-dependent NF-κB signaling — while interaction with Dvl2/Dvl3 co-activates canonical Wnt signaling (PMID:15143197, PMID:21134377, PMID:27134758, PMID:41418976). LPA2 also functions as a radioprotective receptor: its gene is transcriptionally upregulated by γ-irradiation via ATM/NF-κB, and its activation accelerates DNA damage repair and preserves tight junction integrity through Rho-kinase-dependent mechanisms (PMID:26027517, PMID:32654268). In vivo, LPA2 loss reduces colitis-associated colon tumorigenesis by attenuating β-catenin, COX-2, and macrophage infiltration, while endothelial-specific deletion impairs cardiac angiogenesis after myocardial infarction (PMID:19328876, PMID:35920162).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Establishing that LPA2 is a functional multi-pathway GPCR resolved which signaling outputs this receptor activates, demonstrating coupling to PLC/IP production, MAPK, arachidonic acid release, cAMP inhibition, and Ca²⁺ mobilization.

    Evidence Heterologous expression in receptor-null B103 neuroblastoma cells and Ca²⁺/sphingosine kinase assays in SH-SY5Y cells

    PMID:10954727 PMID:11040035

    Open questions at the time
    • Relative contribution of individual G-protein subtypes not resolved
    • No structural information on receptor-G-protein coupling
  2. 2002 High

    Genetic ablation of Lpar1 and Lpar2 in mouse fibroblasts demonstrated functional redundancy between LPA1 and LPA2 for most LPA responses, defining LPA2 as necessary for full LPA signaling when LPA1 is absent.

    Evidence Lpa1⁻/⁻/lpa2⁻/⁻ double-knockout MEFs with multiple signaling readouts

    PMID:12215548

    Open questions at the time
    • Receptor-specific versus shared downstream effectors not delineated
    • In vivo phenotype of lpa2 single knockout not yet characterized
  3. 2004 High

    Discovery of the NHERF2–LPA2–PLC-β3 ternary complex identified the PDZ-binding motif as the molecular determinant of LPA2 signaling specificity, explaining how a broadly coupled GPCR achieves selective effector activation.

    Evidence Co-IP, PDZ motif mutagenesis, and isoform-specific RNAi in HEK293 cells

    PMID:15143197

    Open questions at the time
    • Stoichiometry and dynamics of the ternary complex unknown
    • Whether other PDZ scaffold proteins compete for this motif not yet tested
  4. 2007 High

    Receptor-specific knockdown established that LPA2 activates RhoA to drive breast cancer cell chemotaxis, distinguishing its migration mechanism from LPA1 and revealing G12/13-RhoA as an LPA2-selective pathway arm.

    Evidence LPA2 siRNA, C3 exotransferase, and Transwell assays in BT-20 cells

    PMID:17496233

    Open questions at the time
    • RhoGEF linking LPA2 to RhoA not identified
    • Context-dependence of LPA2 promoting versus inhibiting migration not explained
  5. 2009 High

    Three contemporaneous studies revealed LPA2's diverse in vivo roles: Gαq/RhoA-dependent TGF-β transactivation via αvβ6 integrin in epithelia, G12/13-dependent suppression of EGF-induced migration in pancreatic cancer, and promotion of colon tumorigenesis through β-catenin/COX-2 in knockout mice.

    Evidence Receptor-specific siRNA with pathway inhibitors in bronchial/pancreatic cells; Lpar2⁻/⁻ mice in AOM/DSS colon cancer model

    PMID:19129242 PMID:19147812 PMID:19328876

    Open questions at the time
    • How LPA2 promotes migration in one context but inhibits it in another remains mechanistically unresolved
    • Direct targets linking LPA2 to β-catenin stabilization not identified
  6. 2010 High

    The discovery that MAGI-3 competes with NHERF2 for the LPA2 PDZ motif and shifts G-protein coupling from Gαq toward Gα12 established a scaffold-switching model for bidirectional regulation of LPA2 signaling.

    Evidence Co-IP competition experiments, MAGI-3 overexpression/knockdown with signaling readouts in colon cancer cells

    PMID:21134377

    Open questions at the time
    • What determines the relative abundance of MAGI-3 versus NHERF2 at the receptor in different tissues
    • Whether scaffold switching occurs dynamically in real time
  7. 2012 High

    Identification of the LPA2–NHERF2–TRIP6 antiapoptotic complex and demonstration of LPA2-mediated TGF-β/SMAD-dependent fibrotic signaling in kidney established dual pro-survival and pro-fibrotic effector arms downstream of LPA2.

    Evidence Co-IP in reconstituted LPA1/2-DKO MEFs with LPA2-specific agonist GRI977143; pathway dissection with ROCK/Gαq inhibitors in proximal tubule cells and IRI rat model

    PMID:22885106 PMID:22968304

    Open questions at the time
    • How TRIP6 is recruited to LPA2 (direct or NHERF2-bridged) not fully resolved
    • Whether the antiapoptotic complex operates in non-epithelial cell types unknown
  8. 2014 High

    Single-particle tracking and in vivo neural crest imaging revealed that LPA2 PDZ-dependent complexes are spatially polarized at the leading edge, generating asymmetric Ca²⁺ gradients for chemotaxis and driving N-cadherin internalization for collective cell migration.

    Evidence Single-particle tracking with PDZ mutagenesis in fibroblasts; LPA2 knockdown in Xenopus neural crest with rheological analysis

    PMID:25002680 PMID:25542932

    Open questions at the time
    • Identity of the PDZ scaffold at the leading edge not determined
    • How N-cadherin internalization is mechanistically linked to LPA2 downstream signaling not established
  9. 2014 High

    Crystal structure of NHERF2-PDZ1 bound to the LPA2 C-terminal peptide provided atomic-level understanding of the specificity determinants, revealing hydrogen-bonding and hydrophobic contacts and a druggable surface pocket.

    Evidence X-ray crystallography of NHERF2 PDZ1–LPA2 peptide complex

    PMID:24613836

    Open questions at the time
    • No full-length LPA2 structure in complex with NHERF2
    • Whether the adjacent pocket is functionally exploitable not tested
  10. 2015 High

    Demonstration that LPA2 is a DNA damage-response gene transcriptionally induced by γ-irradiation through ATM/NF-κB, and that LPA2 activation accelerates γ-H2AX resolution via ERK/PI3K-Akt, established a feed-forward radioprotective circuit dependent on the C-terminal interaction motif.

    Evidence LPA2 promoter NF-κB site mutagenesis, ATM inhibitor, γ-H2AX kinetics in LPA2-reconstituted MEFs, Lpar2 KO mice irradiation

    PMID:26027517

    Open questions at the time
    • Direct DNA repair effectors downstream of ERK/Akt in this context not identified
    • Whether this radioprotective mechanism operates in non-intestinal tissues not tested
  11. 2016 High

    Mechanistic dissection of the TRIP6–TRAF6 axis showed TRIP6 sustains LPA2-induced NF-κB signaling by activating TRAF6 E3 ligase activity and antagonizing deubiquitinases A20/CYLD, providing the molecular logic for how the LPA2 C-terminal scaffold drives inflammatory gene expression.

    Evidence Co-IP, CRISPR knockout, and shRNA knockdown of TRIP6/TRAF6 with NF-κB/JNK readouts in ovarian cancer cells

    PMID:27134758

    Open questions at the time
    • Ubiquitin chain types on TRAF6 in LPA2 context not defined
    • Whether TRIP6-TRAF6 engagement is unique to LPA2 or shared with other GPCRs
  12. 2020 High

    Pharmacological agonism and genetic ablation of LPA2 established its role in maintaining epithelial tight junctions after irradiation via Rho-kinase, and in macrophage-mediated inflammation during colitis, broadening its barrier-protective and immunomodulatory functions.

    Evidence Lpar2 KO mice with RP1 agonist in irradiation model; LPA2 siRNA in macrophages and adenoviral shRNA in DSS colitis model

    PMID:32654268 PMID:33128578

    Open questions at the time
    • Which tight junction proteins are direct versus indirect targets of Rho-kinase in this context
    • Macrophage-specific signaling pathway downstream of LPA2 not detailed
  13. 2021 High

    Endothelial-specific Lpar2 knockout phenocopied global knockout in cardiac ischemia, establishing LPA2 as the functionally relevant LPA receptor in cardiac endothelium where it drives angiogenesis through PI3K-Akt/PLC-Raf1-Erk and PKD1-CD36 pathways.

    Evidence Endothelial-specific and global Lpar2 KO, adenoviral rescue, MI models in adult and neonatal mice

    PMID:35920162

    Open questions at the time
    • How PKD1-CD36 signaling mechanistically connects to tube formation not defined
    • Whether LPA2 agonism is therapeutic post-MI not tested in preclinical intervention studies
  14. 2022 High

    LPA2 was shown to protect endothelial barrier function in sepsis through PLC-PKC-FAK signaling that maintains tight and adherens junction proteins, extending the barrier-protective role from epithelial to endothelial contexts.

    Evidence Lpar2 KO mice in LPS-sepsis model, DBIBB agonist, TEER, Evans blue permeability, junction protein analysis in MLMECs

    PMID:38026263

    Open questions at the time
    • Whether FAK is directly phosphorylated by PKC or through an intermediate kinase
    • Endothelial scaffold complex identity (NHERF2 or other) not determined
  15. 2025 High

    Discovery of a PDZ-dependent LPA2–Dvl2/Dvl3 interaction that co-activates canonical Wnt/β-catenin signaling provided a molecular mechanism for the earlier observation that LPA2 loss reduces β-catenin in colon tumors.

    Evidence Co-IP of LPA2 with Dvl2/Dvl3, PDZ-minus mutant, β-catenin reporter and phospho-β-catenin analysis in colon cancer cells

    PMID:41418976

    Open questions at the time
    • Whether LPA2-Dvl interaction occurs through direct PDZ-PDZ binding or requires a bridging scaffold
    • Functional consequence of LPA2-Wnt crosstalk in vivo not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structure of LPA2 in complex with its C-terminal scaffolding partners is lacking, and the rules governing scaffold selection (NHERF2 vs MAGI-3 vs TRIP6 vs Dvl) in different tissue contexts remain undefined.
  • No full-length LPA2 cryo-EM or crystal structure with scaffold bound
  • Tissue-specific determinants of scaffold partner selection unknown
  • Therapeutic window for LPA2 agonism (radioprotection/barrier) versus antagonism (cancer) not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 13 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1266738 Developmental Biology 1 R-HSA-73894 DNA Repair 1
Partners
CFTRDVL2DVL3MAGI-3NHERF2PLC-Β3TRAF6TRIP6
Complex memberships
LPA2–NHERF2–PLC-β3LPA2–NHERF2–TRIP6TRIP6–TRAF6

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 LPA2 (EDG4/LP(A2)) couples to multiple G-proteins and mediates LPA-dependent inositol phosphate production, MAPK activation, arachidonic acid release, and inhibition of forskolin-induced cAMP accumulation in neuronal cell lines; LPA2 expression induces cell rounding in neuroblastoma cells. Retrovirus-mediated heterologous expression in B103 neuroblastoma cells lacking endogenous LPA receptors, followed by functional signaling assays Molecular pharmacology High 11040035
2000 In human SH-SY5Y neuroblastoma cells, LPA2 (Edg-4) mediates Ca2+ mobilization via production of intracellular sphingosine 1-phosphate (S1P) through sphingosine kinase, independent of Ins(1,4,5)P3 receptor-mediated Ca2+ release, with subsequent interaction between the S1P pathway and IP3 receptors. Pharmacological inhibition of sphingosine kinase, 45Ca2+ release assays in permeabilized cells, confocal microscopy of Ca2+ puffs, [3H]S1P production measurement The Journal of biological chemistry High 10954727
2002 LPA2 acts redundantly with LPA1 to mediate most LPA responses in fibroblasts, including phospholipase C activation, Ca2+ mobilization, adenylyl cyclase activation, proliferation, JNK activation, Akt activation, and stress fiber formation, as demonstrated in lpa1(-/-)/lpa2(-/-) double-knockout mouse embryonic fibroblasts. Genetic knockout (lpa2-/- and lpa1-/-/lpa2-/- mice), MEF functional assays for PLC, Ca2+, cAMP, proliferation, JNK, Akt, and cytoskeletal responses Molecular and cellular biology High 12215548
2004 LPA2 specifically interacts via its C-terminal PDZ-binding motif with the second PDZ domain of NHERF2, which scaffolds a ternary complex (LPA2–NHERF2–PLC-β3), thereby specifically potentiating LPA-induced PLC-β3 activation and downstream ERK activation leading to COX-2 induction. Co-immunoprecipitation, PDZ-binding motif mutagenesis, RNA interference of NHERF2 and PLC-β3 isoforms, stable expression in HEK293 cells Molecular and cellular biology High 15143197
2005 In human colon cancer cells, LPA2 activates Akt via Gi-protein and ERK1/2 via PLCβ, and mediates IL-8 synthesis; LPA2 directly interacts with NHERF2, which is required for efficient Akt and ERK1/2 activation. Pertussis toxin inhibition, PLCβ inhibitor (U-73122), Co-IP of LPA2 and NHERF2, NHERF2 siRNA knockdown, LPA2 siRNA American journal of physiology. Cell physiology High 15728708
2007 LPA2 mediates Rho-dependent chemotaxis in breast cancer cells with lower efficacy than LPA1; LPA2 specifically activates RhoA to promote cell migration, as demonstrated by LPA2-specific siRNA and C3 exotransferase treatment in BT-20 cells. LPA2-specific siRNA, C3 exotransferase (RhoA inhibitor), LPA1 exogenous expression, Ki16425 antagonist, Transwell chemotaxis assay American journal of physiology. Cell physiology High 17496233
2008 LPA2 C-terminal tail contains at least two protein interaction motifs mediating PDZ-protein interactions (e.g., NHERF2, MAGI-3) and zinc finger protein interactions (e.g., TRIP6), which regulate the specificity and efficiency of LPA2-mediated signaling. Review/summary of biochemical protein-protein interaction studies (Co-IP, PDZ binding motif mapping) Biochimica et biophysica acta Medium 18501721
2009 LPA-induced αvβ6 integrin-mediated TGF-β activation in epithelial cells is mediated specifically via LPA2 receptor signaling through Gαq, RhoA, and Rho kinase. LPA2-specific siRNA knockdown, Gαq pathway inhibition, RhoA and Rho kinase inhibitors, TGF-β bioassay in human bronchial epithelial cells The American journal of pathology High 19147812
2009 LPA2 couples to the G12/13/Rho signaling pathway (not Gi) to inhibit EGF-induced migration and invasion of pancreatic cancer cells, contrasting with LPA1-mediated stimulation of migration. LPA2-specific siRNA, pertussis toxin (Gi inhibitor), LP-105 LPA2-specific agonist, RhoA-dominant negative and C3 toxin, Transwell and Matrigel invasion assays Carcinogenesis High 19129242
2009 LPA2 absence reduces colon tumor formation by attenuating epithelial proliferation and decreasing β-catenin, KLF5, COX-2 expression, and macrophage infiltration via monocyte chemoattractant protein-1 and macrophage migration inhibitory factor. LPA2 knockout mice in azoxymethane/DSS colitis-associated cancer model, LPA treatment in Apc(min/+) mice, IHC and molecular marker analysis Gastroenterology High 19328876
2010 MAGI-3 competes with NHERF-2 for binding to LPA2 and PLC-β3: MAGI-3 binding shifts G-protein coupling toward Gα12 (inhibitory signaling), while NHERF-2 promotes Gαq coupling (stimulatory PLC signaling), thereby opposing effects on LPA2-mediated migration, invasion, and NF-κB activation. Co-IP of LPA2 with MAGI-3, NHERF-2, Gα12, Gαq; MAGI-3 overexpression and knockdown; inositol phosphate production assay; cell migration and invasion assays in HCT116 and SW480 Gastroenterology High 21134377
2011 LPA stimulates DRA (SLC26A3) gene transcription through the LPA2 receptor via a PI3K/AKT and c-Fos-dependent pathway acting on the -1183/-790 region of the DRA promoter. LPA2 siRNA knockdown, PI3K inhibitor, DRA promoter deletion constructs/reporter assays, EMSA, c-Fos overexpression and siRNA in Caco-2 cells American journal of physiology. Gastrointestinal and liver physiology High 22159277
2012 LPA2 mediates proximal tubule cell secretion of PDGF-B and CTGF through Gαq, Rho/Rho-kinase, and αvβ6 integrin-dependent transactivation of latent TGF-β, which then activates SMAD signaling to upregulate these profibrotic cytokines. LPA2 siRNA, Gαq inhibition, Rho/ROCK inhibitors, αvβ6 integrin blocking antibody, TGF-β bioassays, SMAD signaling analysis, ischemia-reperfusion injury rat model The American journal of pathology High 22885106
2012 LPA2 activation promotes an antiapoptotic signaling complex comprising LPA2, NHERF2, and TRIP6 (thyroid receptor interacting protein 6); non-lipid LPA2-specific agonist GRI977143 assembles this complex and activates ERK1/2 prosurvival signaling, reducing caspase activation and DNA fragmentation. Co-IP of LPA2–NHERF2–TRIP6 complex, MEF cells from LPA1&2-DKO reconstituted with LPA2, caspase activity assays, PARP cleavage, DNA fragmentation, ERK1/2 phosphorylation Molecular pharmacology High 22968304
2014 LPA2 mediates collective cell migration of neural crest cells in vivo by promoting N-cadherin internalization downstream of LPA, reducing cell-cell adhesion and increasing tissue fluidity to allow a solid-to-fluid-like transition while maintaining collective behavior. In vivo neural crest imaging (Xenopus), LPA2 inhibition/knockdown, N-cadherin trafficking assays, rheological analysis of tissue fluidity The Journal of cell biology High 25002680
2014 LPA2 forms spatiotemporally restricted, asymmetric macromolecular complexes via PDZ motif-mediated interactions at the leading edge of chemotacting fibroblasts, triggering localized Ca2+ puff gradients that govern gradient sensing and directional migration toward LPA. Single-particle tracking of LPA2 mobility, PDZ motif mutagenesis, Ca2+ imaging, directional migration assays in fibroblasts The Journal of biological chemistry High 25542932
2014 Crystal structure of NHERF2 PDZ1 domain in complex with the C-terminal LPA2 peptide reveals that binding specificity is achieved through hydrogen bonds and hydrophobic contacts with the last four LPA2 residues, and identifies a small surface pocket adjacent to the binding site. X-ray crystallography of NHERF2 PDZ1–LPA2 C-terminal peptide complex Biochemical and biophysical research communications High 24613836
2015 The autotaxin-LPA2 axis is upregulated by γ-irradiation via an ATM/NF-κB-dependent mechanism; LPA2 activation accelerates DNA damage repair (resolution of γ-H2AX) through ERK1/2 and PI3K/AKT pathways, and the C-terminus of LPA2 (C311A/C314A/L351A mutation) is required for this effect. qRT-PCR, NF-κB site mutagenesis in lpa2 promoter, ATM/ATR kinase inhibitor (CGK-733), γ-H2AX kinetics in LPA2-reconstituted MEF cells, pertussis toxin, C-terminal LPA2 mutagenesis, Lpar2 KO mice irradiation model Cellular signalling High 26027517
2016 TRIP6 functions as a positive regulator of LPA2-induced NF-κB and JNK signaling by directly binding and activating the E3 ligase TRAF6 upon LPA stimulation; TRIP6 antagonizes recruitment of deubiquitinases A20 and CYLD to TRAF6, sustaining its E3 ligase activity. Conversely, TRAF6 promotes TRIP6 phosphorylation by c-Src and its binding to NF-κB p65. Co-IP of TRIP6–TRAF6–LPA2, TRIP6 shRNA and CRISPR/sgRNA knockdown, TRAF6 siRNA, overexpression assays, NF-κB and JNK/p38 activation assays in ovarian cancer cells Cell discovery High 27134758
2017 LPA2 forms a macromolecular complex with CFTR and NHERF2 at the apical plasma membrane of airway and gut epithelial cells; disruption of the PDZ-mediated NHERF2–LPA2 interaction abolishes the LPA inhibitory effect on CFTR Cl- channel activity. Co-IP, PDZ motif disruption, CFTR channel activity measurements (reviewed with prior functional data) International journal of molecular sciences Medium 28869532
2018 LPA2 mediates LPA-induced ovarian cancer cell migration via phosphorylation of ERM (ezrin/radixin/moesin) proteins at their C-termini through the Gα12/13/RhoA pathway; gene silencing of LPA2 or expression of dominant-negative ezrin completely abolishes LPA-induced migration. LPA receptor siRNA knockdown, Gα pathway inhibitors, ERM phosphorylation western blot, dominant-negative ezrin-T567A overexpression, Transwell migration assay in OVCAR-3 cells Cellular signalling High 29329782
2020 LPA2 receptor agonism reduces γ-irradiation-induced disruption of colonic epithelial tight junction proteins via a Rho-kinase-dependent mechanism, protecting mucosal barrier function and reducing endotoxemia; Lpar2-/- mice show more severe TJ disruption after irradiation than wild-type mice. Lpar2 KO mice, LPA2 agonist RP1 (Radioprotectin-1), ROCK inhibitor, immunofluorescence of TJ proteins, mucosal permeability (inulin), plasma LPS measurement, actin cytoskeleton imaging FASEB journal High 32654268
2021 LPA2 receptor activation promotes endothelial cell proliferation through PI3K-Akt/PLC-Raf1-Erk signaling and enhances tube formation via PKD1-CD36 signaling; endothelial-specific LPA2 knockout phenocopies global knockout in cardiac ischemia, establishing LPA2 as the relevant LPA receptor in cardiac endothelial cells after MI. Global and endothelial-specific Lpar2 KO mice, adenovirus-mediated Lpar2 overexpression, pharmacological LPA2 activation, MI models (adult and neonatal), PI3K/Akt/PLC/ERK pathway inhibition, tube formation assays Circulation research High 35920162
2021 Proximal tubule LPA1 and LPA2 receptors use divergent signaling pathways (LPA2 via Gαq-αvβ6-TGF-β1/SMAD; LPA1 via EGFR-ERK1/2-AP-1) that additively increase PDGF-B and CTGF production; autotaxin inhibition suppresses both pathways. Pathway-specific inhibitors for each arm, autotaxin inhibitor, dual receptor knockdown/inhibition, SMAD and ERK signaling readouts in proximal tubule cells and IRI kidneys American journal of physiology. Renal physiology High 33427061
2022 Endothelial LPA2 protects vascular barrier function in septic ALI through the PLC-PKC-FAK signaling pathway, maintaining tight junction (ZO-1, claudin-5) and adherens junction (VE-cadherin) protein expression. Lpar2 KO mice (LPS-induced sepsis model), DBIBB LPA2 agonist, transendothelial electrical resistance (TEER), Evans blue dye permeability, Western blot of junction proteins, PLC/PKC/FAK pathway analysis in MLMECs Journal of inflammation research High 38026263
2025 LPA2 interacts via its PDZ-binding motif in its carboxyl terminus with Dishevelled proteins Dvl2 and Dvl3 in colon cancer cells, co-activating canonical Wnt/β-catenin signaling (S552 and S675 phosphorylation, β-catenin transcriptional activity) in a non-additive manner with Wnt-3a; mutation of the LPA2 PDZ motif (LPA2-PDZminus) disrupts this interaction and impairs canonical Wnt signaling activation. Co-immunoprecipitation of LPA2 with Dvl2/Dvl3, LPA2-PDZminus mutant expression, β-catenin reporter assay, phospho-β-catenin Western blot, cell migration and proliferation assays Cellular signalling High 41418976
2015 LPA2 receptor phosphorylation requires higher concentrations of LPA or PKC activators than LPA1/LPA3, and its internalization is less intense; homologous desensitization of LPA2 occurs independently of PKC. LPA2-mediated ERK1/2 phosphorylation involves EGF receptor transactivation. Stably expressed LPA1, LPA2, LPA3 in C9 cells; phorbol ester (PMA) and bisindolylmaleimide I treatment; PKC down-regulation; EGFR tyrosine kinase inhibitor; intracellular Ca2+ assay; ERK phosphorylation PloS one Medium 26473723
2020 LPA2 signaling in macrophages mediates ATX/LPA-induced pro-inflammatory cytokine production; LPA2 gene silencing in RAW264.7 macrophages reduces inflammatory cytokine output, and adenoviral lpa2 shRNA delivery ameliorates DSS-induced colitis in mice. LPA2 siRNA in RAW264.7 and BMDM, adenoviral lpa2 shRNA in DSS colitis mouse model, cytokine ELISA, qRT-PCR of LPA2 expression Journal of molecular medicine Medium 33128578
2019 LPA2 mediates LPA-induced migration and invasion of gastric cancer cells through activation of Notch1 signaling and PI3K/AKT phosphorylation; LPA2 physically interacts with Notch1 as shown by co-immunoprecipitation. LPA2 and Notch1 siRNA knockdown, Transwell migration/invasion assays, immunoprecipitation of LPA2-Notch1 complex, EMT marker analysis in SGC-7901 cells International journal of molecular medicine Medium 31115486
2021 LPA2 interacts with GPR55 in live cells (BRET analysis); co-activation of LPA2 and GPR55 leads to co-internalization, synergistic reduction in intracellular cAMP, and synergistic promotion of cell proliferation and cancer gene expression. BRET (bioluminescence resonance energy transfer) in live cells, co-internalization imaging, cAMP measurement, cell proliferation assay FEBS letters Medium 33959968

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2). Molecular and cellular biology 262 12215548
2009 Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q). The American journal of pathology 176 19147812
2000 Functional comparisons of the lysophosphatidic acid receptors, LP(A1)/VZG-1/EDG-2, LP(A2)/EDG-4, and LP(A3)/EDG-7 in neuronal cell lines using a retrovirus expression system. Molecular pharmacology 164 11040035
2003 The maize low-phytic acid mutant lpa2 is caused by mutation in an inositol phosphate kinase gene. Plant physiology 123 12586875
2009 The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer. Gastroenterology 108 19328876
2014 In vivo collective cell migration requires an LPAR2-dependent increase in tissue fluidity. The Journal of cell biology 106 25002680
2005 LPA2 receptor mediates mitogenic signals in human colon cancer cells. American journal of physiology. Cell physiology 96 15728708
2012 Lysophosphatidic acid increases proximal tubule cell secretion of profibrotic cytokines PDGF-B and CTGF through LPA2- and Gαq-mediated Rho and αvβ6 integrin-dependent activation of TGF-β. The American journal of pathology 83 22885106
2001 Lysophosphatidic acid, a novel lipid growth factor for human thyroid cells: over-expression of the high-affinity receptor edg4 in differentiated thyroid cancer. International journal of cancer 78 11291053
2007 LPA2 (EDG4) mediates Rho-dependent chemotaxis with lower efficacy than LPA1 (EDG2) in breast carcinoma cells. American journal of physiology. Cell physiology 77 17496233
2004 NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation. Molecular and cellular biology 75 15143197
2000 Lysophosphatidic acid-induced Ca2+ mobilization requires intracellular sphingosine 1-phosphate production. Potential involvement of endogenous EDG-4 receptors. The Journal of biological chemistry 65 10954727
2007 LPA2 is required for efficient assembly of photosystem II in Arabidopsis thaliana. The Plant cell 64 17601825
2000 Genomic characterization of the lysophosphatidic acid receptor gene, lp(A2)/Edg4, and identification of a frameshift mutation in a previously characterized cDNA. Genomics 59 10729222
2012 Virtual screening for LPA2-specific agonists identifies a nonlipid compound with antiapoptotic actions. Molecular pharmacology 56 22968304
2009 LPA1 receptors mediate stimulation, whereas LPA2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites. Carcinogenesis 56 19129242
2010 MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells. Gastroenterology 53 21134377
2022 LPA2 Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction. Circulation research 51 35920162
2009 Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma. Respiratory research 51 19930563
2004 Induction of protein growth factor systems in the ovaries of transgenic mice overexpressing human type 2 lysophosphatidic acid G protein-coupled receptor (LPA2). Oncogene 47 14712217
2014 Regulation of T cell motility in vitro and in vivo by LPA and LPA2. PloS one 46 25003200
2012 Lpa2 is a negative regulator of both dendritic cell activation and murine models of allergic lung inflammation. Journal of immunology (Baltimore, Md. : 1950) 46 22427635
2019 LPA1 , LPA2 , LPA4 , and LPA6 receptor expression during mouse brain development. Developmental dynamics : an official publication of the American Association of Anatomists 43 30847983
2015 The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair. Cellular signalling 42 26027517
2018 LPA-induced migration of ovarian cancer cells requires activation of ERM proteins via LPA1 and LPA2. Cellular signalling 38 29329782
2010 Cooperation of LPA3 and LPA2 is essential for photosystem II assembly in Arabidopsis. Plant physiology 37 20605914
2015 Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist. Chemistry & biology 34 25619933
2016 Higher LPA2 and LPA6 mRNA Levels in Hepatocellular Carcinoma Are Associated with Poorer Differentiation, Microvascular Invasion and Earlier Recurrence with Higher Serum Autotaxin Levels. PloS one 33 27583415
2008 Discovery of potent LPA2 (EDG4) antagonists as potential anticancer agents. Bioorganic & medicinal chemistry letters 33 18178086
2009 Lysophosphatidic acid-induced arterial wall remodeling: requirement of PPARgamma but not LPA1 or LPA2 GPCR. Cellular signalling 32 19709640
2019 Lysophosphatidic acid induces the migration and invasion of SGC-7901 gastric cancer cells through the LPA2 and Notch signaling pathways. International journal of molecular medicine 30 31115486
2013 Mitigation of radiation injury by selective stimulation of the LPA(2) receptor. Biochimica et biophysica acta 30 23127512
2017 Lysophosphatidic Acid Is Associated with Atherosclerotic Plaque Instability by Regulating NF-κB Dependent Matrix Metalloproteinase-9 Expression via LPA2 in Macrophages. Frontiers in physiology 29 28496416
2020 Effects of lysophosphatidic acid (LPA) receptor-2 (LPA2) and LPA3 on the regulation of chemoresistance to anticancer drug in lung cancer cells. Cellular signalling 28 32006610
2011 LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3K/AKT, and c-Fos-dependent pathway. American journal of physiology. Gastrointestinal and liver physiology 24 22159277
2008 Regulation of the LPA2 receptor signaling through the carboxyl-terminal tail-mediated protein-protein interactions. Biochimica et biophysica acta 24 18501721
2020 Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2. Cellular and molecular life sciences : CMLS 21 32468095
2015 Phosphorylation and Internalization of Lysophosphatidic Acid Receptors LPA1, LPA2, and LPA3. PloS one 21 26473723
2020 Lysophosphatidic Acid Induces Apoptosis of PC12 Cells Through LPA1 Receptor/LPA2 Receptor/MAPK Signaling Pathway. Frontiers in molecular neuroscience 20 32116549
2018 The LPA2 receptor agonist Radioprotectin-1 spares Lgr5-positive intestinal stem cells from radiation injury in murine enteroids. Cellular signalling 19 30063964
2016 TRIP6 antagonizes the recruitment of A20 and CYLD to TRAF6 to promote the LPA2 receptor-mediated TRAF6 activation. Cell discovery 18 27134758
2008 Lysophosphatidic acid stimulates the proliferation and motility of malignant pleural mesothelioma cells through lysophosphatidic acid receptors, LPA1 and LPA2. Cancer science 18 18754873
2005 Differential effects of lysolipids on steroid synthesis in cells expressing endogenous LPA2 receptor. Journal of lipid research 17 15716590
2023 Combined inhibition of EZH2 and the autotaxin-LPA-LPA2 axis exerts synergistic antitumor effects on colon cancer cells. Cancer letters 16 37230222
2020 LPAR2 receptor activation attenuates radiation-induced disruption of apical junctional complexes and mucosal barrier dysfunction in mouse colon. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 32654268
2017 Enhanced cellular functions through induction of LPA2 by cisplatin in fibrosarcoma HT1080 cells. Molecular and cellular biochemistry 16 28205098
2022 Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice. International journal of molecular sciences 15 36077141
2021 LPA2 protein is involved in photosystem II assembly in Chlamydomonas reinhardtii. The Plant journal : for cell and molecular biology 15 34218480
2021 Gintonin regulates inflammation in human IL-1β-stimulated fibroblast-like synoviocytes and carrageenan/kaolin-induced arthritis in rats through LPAR2. Journal of ginseng research 14 34803427
2022 Berberine inhibits carcinogenesis through antagonizing the ATX-LPA-LPAR2-p38-leptin axis in a mouse hepatoma model. Molecular therapy oncolytics 13 36090480
2021 Dual Role of Lysophosphatidic Acid Receptor 2 (LPA2) in Amyotrophic Lateral Sclerosis. Frontiers in cellular neuroscience 13 33841099
2020 Autotaxin stimulates LPA2 receptor in macrophages and exacerbates dextran sulfate sodium-induced acute colitis. Journal of molecular medicine (Berlin, Germany) 13 33128578
2021 Proximal tubule LPA1 and LPA2 receptors use divergent signaling pathways to additively increase profibrotic cytokine secretion. American journal of physiology. Renal physiology 12 33427061
2021 Phosphatidic Acid Stimulates Myoblast Proliferation through Interaction with LPA1 and LPA2 Receptors. International journal of molecular sciences 12 33535610
2018 Lysophosphatidic acid receptor-2 (LPA2) and LPA5 regulate cellular functions during tumor progression in fibrosarcoma HT1080 cells. Biochemical and biophysical research communications 12 30093116
2017 CFTR-NHERF2-LPA₂ Complex in the Airway and Gut Epithelia. International journal of molecular sciences 12 28869532
2014 Design and synthesis of sulfamoyl benzoic acid analogues with subnanomolar agonist activity specific to the LPA2 receptor. Journal of medicinal chemistry 12 25100502
2014 Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation. Biochemical and biophysical research communications 11 24613836
1996 Direct and modulatory effects of FMRFamide, SKPYMRFamide and acety1-SKPYMRFamide on LPa2, LPa3, and RPa3 identified neurons of Helix lucorum. Regulatory peptides 11 8988517
2022 Compensatory Upregulation of LPA2 and Activation of the PI3K-Akt Pathway Prevent LPA5-Dependent Loss of Intestinal Epithelial Cells in Intestinal Organoids. Cells 10 35883686
2020 Cooperation of G12/13 and Gi proteins via lysophosphatidic acid receptor-2 (LPA2) signaling enhances cancer cell survival to cisplatin. Biochemical and biophysical research communications 10 32883524
2007 Alkoxymethylenephosphonate analogues of (Lyso) phosphatidic acid stimulate signaling networks coupled to the LPA2 receptor. ChemMedChem 10 17952880
2022 Alteration of Cellular Energy Metabolism through LPAR2-Axin2 Axis in Gastric Cancer. Biomolecules 9 36551233
2020 Development and validation of breeder-friendly gene-based markers for lpa1-1 and lpa2-1 genes conferring low phytic acid in maize kernel. 3 Biotech 9 32123645
2020 Different effects of lysophosphatidic acid receptor-2 (LPA2) and LPA5 on the regulation of chemoresistance in colon cancer cells. Journal of receptor and signal transduction research 9 32672083
2018 LPAR2 and LPAR4 are the Main Receptors Responsible for LPA Actions in Ovarian Endometriotic Cysts. Reproductive sciences (Thousand Oaks, Calif.) 9 29621954
2014 Asymmetrical macromolecular complex formation of lysophosphatidic acid receptor 2 (LPA2) mediates gradient sensing in fibroblasts. The Journal of biological chemistry 8 25542932
2022 Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice. Journal of medicinal chemistry 7 35948083
2020 Roles of endothelial cells in the regulation of cell motility via lysophosphatidic acid receptor-2 (LPA2) and LPA3 in osteosarcoma cells. Experimental and molecular pathology 7 33347862
2023 Roles of lysophosphatidic acid (LPA) receptor-2 (LPA2) in the regulation of cellular responses induced by X-ray irradiation and hydrogen peroxide in pancreatic cancer cells. International journal of radiation biology 6 37523658
2022 LPA2 promotes neuronal differentiation and neurite formation in neocortical development. Biochemical and biophysical research communications 6 35151977
2021 Interplay between LPA2 and LPA3 in LPA-mediated phosphatidylserine cell surface exposure and extracellular vesicles release by erythrocytes. Biochemical pharmacology 6 34216604
2021 BRET analysis reveals interaction between the lysophosphatidic acid receptor LPA2 and the lysophosphatidylinositol receptor GPR55 in live cells. FEBS letters 5 33959968
2016 Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia. PloS one 5 27124742
2015 NT-3 protein levels are enhanced in the hippocampus of PRG1-deficient mice but remain unchanged in PRG1/LPA2 double mutants. Neuroscience letters 5 26687273
2002 Native and recombinant human Edg4 receptor-mediated Ca(2+) signalling. Assay and drug development technologies 5 15090154
2023 A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy. Acta pharmacologica Sinica 4 37816857
2022 LPAR2-mediated action promotes human renal cell carcinoma via MAPK/NF-κB signaling to regulate cytokine network. Journal of cancer research and clinical oncology 4 35857125
2007 [Expression and significance of Edg4 and Edg7 in the placentas of patients with hypertensive disorder complicating pregnancy]. Zhonghua fu chan ke za zhi 4 17697599
2023 LPA2 Alleviates Septic Acute Lung Injury via Protective Endothelial Barrier Function Through Activation of PLC-PKC-FAK. Journal of inflammation research 3 38026263
2008 Full-length coding sequences, polymorphism and chromosomal localizations of the porcine EDG4 and EDG7 genes. Molecular biology reports 3 18379896
2022 Estrogen-increased SGK1 Promotes Endometrial Stromal Cell Invasion in Adenomyosis by Regulating with LPAR2. Reproductive sciences (Thousand Oaks, Calif.) 2 35799024
2025 Spatiotemporal expression of lpa1 and lpa2 genes showed low phytate accumulation in maize foliage and seeds during early developmental stages. Plant physiology and biochemistry : PPB 1 41138698
2025 Inhibition of autotaxin sensitizes colon cancer to radiation by suppressing LPAR2-AKT survival signaling. BMC gastroenterology 1 41454227
2024 A mutation in LPAR2 activates the miR-939-5p-LPAR2-PI3K/AKT axis to regulate the proliferation and apoptosis of granulosa cells in sheep. Theriogenology 1 38368704
2024 Circ_0007611 modulates the miR-34c-5p/LPAR2 cascade to suppress proliferation and enhance apoptosis of HTR-8/SVneo cells. Placenta 1 38986295
2024 Lysophosphatidic Acid Receptors LPAR5 and LPAR2 Inversely Control Hydroxychloroquine-Evoked Itch and Scratching in Mice. International journal of molecular sciences 1 39125747
2023 Differential targeting of lysophosphatidic acid LPA1, LPA2, and LPA3 receptor signalling by tricyclic and tetracyclic antidepressants. European journal of pharmacology 1 37758013
2025 The LPA2 receptor PDZ domain affects canonical Wnt signaling in colon cancer cells. Cellular signalling 0 41418976
2025 Engineering Native-like GPCR Antigens Enables Discovery of an LPA2-Blocking Antibody for Ovarian Cancer. ACS synthetic biology 0 41476039
2024 Regulation of cellular responses to X-ray irradiation through the activation of lysophosphatidic acid (LPA) receptor-3 (LPA3) and LPA2 in osteosarcoma cells. Pathology, research and practice 0 38615508
2007 [Vector construction and silencing effect of Edg4 gene targeted small interfering RNA in ovarian cancer cell line]. Zhonghua fu chan ke za zhi 0 18307905