Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways.
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The source is a large-scale human cDNA reporter screen for activators of NF-kappaB and MAPK pathways; its accessible abstract does not identify LPAR1 individually.
"We have carried out a large-scale identification and characterization of human genes that activate the NF-kappaB and MARK signaling pathways."
Complete sequencing and characterization of 21,243 full-length human cDNAs.
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This large-scale human cDNA sequencing project is the sequence source underlying UniProt's second LPAR1 transcript model, not a functional isoform comparison.
"We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection."
Dual regulation of lysophosphatidic acid (LPA1) receptor signalling by Ral and GRK.
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In HEK293 cells, LPA1 associates with RalA; LPA stimulation activates RalA and promotes Ral-dependent phospholipase C activity.
"We show that the small GTPase RalA associates with both LPA(1) and LPA(2) in human embryonic kidney (HEK 293) cells and that stimulation of LPA(1) receptors with LPA triggers the activation of RalA."
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GRK2 is required for LPA1 desensitization and forms an activity-promoted complex with RalA.
"Furthermore, we found that GRK2 is required for the desensitization of LPA(1) and LPA(2) and have identified a novel interaction between RalA and GRK2, which is promoted by LPA(1) receptor activity."
Lysophosphatidic acid mediates migration of human mesenchymal stem cells stimulated by synovial fluid of patients with rheumatoid arthritis.
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Endogenous LPA1 is required for rheumatoid-arthritis synovial-fluid-induced human mesenchymal stem-cell migration and acts through calcium/calmodulin-dependent kinase II.
"These results suggest that LPA-LPA(1) plays a key role in the migration of hBMSCs induced by SF from RA patients through LPA(1)-dependent activation of calmodulin-dependent protein kinase II."
Molecular regulation of lysophosphatidic acid receptor 1 trafficking to the cell surface.
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Tyr85, Leu87, and Ile325 are required for LPA1 maturation and cell-surface trafficking; disruptive mutants remain predominantly in the ER.
"Further, site-directed mutagenesis analysis of the LPA1 revealed that Ile325, Tyr85, and Leu87 within these two fragments regulate LPA1 maturation and trafficking to the cell surface."
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Trafficking-defective LPA1 mutants fail to activate ERK or cytokine release after LPA.
"Further, we found that all these mutants failed to increase phosphorylation of Erk, and the cytokine release in response to LPA treatment."
Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1.
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Three antagonist-bound human LPA1 crystal structures define the receptor's ligand pocket.
"Herein, we present three crystal structures of LPA1 in complex with antagonist tool compounds selected and designed through structural and stability analyses."
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Structural and molecular-dynamics analysis supports ligand access from the extracellular space.
"Structural analysis combined with molecular dynamics identified a basis for ligand access to the LPA1 binding pocket from the extracellular space contrasting with the proposed access for the sphingosine 1-phosphate receptor."
Akt Regulates a Rab11-Effector Switch Required for Ciliogenesis.
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LPA signaling through LPAR1 inhibits ciliogenesis initiation through PI3K/Akt and a Rab11-effector switch.
"Here, we demonstrate that through the LPA receptor 1 (LPAR1), serum lysophosphatidic acid (LPA) inhibits Rab11a-Rabin8 interaction and ciliogenesis. LPA/LPAR1 regulates ciliogenesis initiation via downstream PI3K/Akt activation, independent of effects on cell cycle."
Quantitative fragmentomics allow affinity mapping of interactomes.
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The paper measures affinities between PDZ domains and PDZ-binding motifs at interactome scale rather than establishing a receptor-signaling function for LPAR1.
"Here, we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer."
LPA receptor 1 (LPAR1) is a novel interaction partner of Filamin A that promotes Filamin A phosphorylation, MRTF-A transcriptional activity and oncogene-induced senescence.
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LPAR1 interacts with FLNA and MRTF-A in HCC cells and organoids.
"We identified the G protein-coupled lysophosphatidic acid receptor 1 (LPAR1) as a novel interaction partner of MRTF-A and Filamin A (FLNA) using fluorescence resonance energy transfer-(FRET) and proximity ligation assay (PLA) in vitro in HCC cells and in vivo in organoids."
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LPAR1 promotes FLNA Ser2152 phosphorylation, FLNA-MRTF-A complex formation, actin polymerization, and MRTF transcriptional activity.
"We found that LPAR1 promotes FLNA phosphorylation at S2152 which enhances the complex formation of FLNA and MRTF-A, actin polymerization, and MRTF transcriptional activity."
Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins.
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A multiplexed screen found strong evidence for RAMP association across 122 GPCRs.
"Screening the GPCR-RAMP pairs with customized multiplexed suspension bead array (SBA) immunoassays, we identified 122 GPCRs that showed strong evidence for interaction with at least one RAMP."
Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex.
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Vzg-1/Lpar1 overexpression increases specific LPA binding and sensitizes Gi activation and cell rounding to LPA.
"Vzg-1 overexpression decreased the EC50 of both cell rounding and Gi activation in response to LPA. Pertussis toxin treatment inhibited vzg-1-dependent LPA-mediated Gi activation, but had no effect on cell rounding. Membrane binding studies indicated that vzg-1 overexpression increased specific LPA binding."
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Vzg-1 expression is enriched in cortical neurogenic regions, suggesting a developmental role for LPA signaling in cortical neurogenesis.
"These analyses identify the vzg-1 gene product as a receptor for LPA, suggesting the operation of LPA signaling mechanisms in cortical neurogenesis."
Molecular cloning of the human Edg2 protein and its identification as a functional cellular receptor for lysophosphatidic acid.
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Human EDG2/LPAR1 expression confers concentration-dependent, LPA-selective signaling and increases specific radiolabeled-LPA binding.
"HEK293 cells expressing the human Edg2 protein showed an elevated response to lysophosphatidic acid (LPA) in a serum response element reporter gene assay, which was LPA concentration-dependent and specific to LPA compared to other lysophospholipids. Over-expression of human Edg2 in CHO cells correlated with increases in specific binding of [3H]-LPA."
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Human EDG2 mRNA is broadly distributed, with highest abundance in brain.
"Human Edg2 mRNA is widely distributed in human tissues with the highest abundance in brain."
Recombinant human G protein-coupled lysophosphatidic acid receptors mediate intracellular calcium mobilization.
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Recombinant human EDG2/LPAR1 mediates LPA-dependent intracellular calcium mobilization through PLC-generated IP3.
"The coincident production of inositol phosphates and the inhibition of Ca2+ mobilization by the phospholipase C inhibitor U73122 strongly suggested that Edg2 and Edg4 mobilize Ca2+ through inositol trisphosphate generated by phospholipase C activation."
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EDG2 calcium signaling is largely mediated by pertussis-toxin-sensitive Gi proteins.
"Pertussis toxin almost completely blocked LPA-induced Ca2+ mobilization by Edg2 but only partially blocked that by Edg4, which suggests that Edg2 transduces Ca2+ mobilization largely through pertussis toxin-sensitive Gi proteins, whereas Edg4 requires both Gi and Gq."
Liganded Gq/11-activating GPCRs act as GEFs for Gq/11
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Reactome models liganded Gq/11-coupled receptors as activating PLC, IP3/DAG, and cytosolic calcium signaling.
"PLC hydrolyzes phosphatidylinositol (PIP2) to diacyl glycerol (DAG) and inositol triphosphate (IP3)."
Liganded Gi-activating GPCR acts as a GEF for Gi
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Reactome models liganded Gi-coupled receptors as stimulating GDP-GTP exchange on the G-alpha subunit.
"This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein."
LPA-binding receptors bind LPA
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Reactome identifies human EDG2 as LPA1, an LPA-binding GPCR, and links its downstream signaling to Gi.
"EDG2 is a human gene encoding a GPCR, LPA1 (as this receptor binds LPA) (An S et al, 1997). Downstream effects such as inhibition of adenylyl cyclase are mediated by binding to Gi proteins (An S et al, 1998)."
Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq
The Ligand:GPCR:Gq complex dissociates
The Ligand:GPCR:Gi complex dissociates
Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi
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Reactome models Gi alpha as inhibiting cAMP production and thereby decreasing PKA activity.
"The G-alpha (i) subunit inhibits the production of cAMP from ATP. In turn, this results in decreased activity of cAMP-dependent protein kinase."
UniProtKB entry Q92633 (LPAR1_HUMAN), lysophosphatidic acid receptor 1
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UniProt summarizes LPAR1 as an LPA receptor coupled to Gi/Go, G12/G13, and Gq-family heterotrimeric G proteins.
"G(i)/G(o), G(12)/G(13), and G(q) families of"
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UniProt records two named alternatively spliced LPAR1 isoforms.
"Event=Alternative splicing; Named isoforms=2;"