Gene Ontology annotation through association of InterPro records with GO terms
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
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid.
-
A cloned human EDG7 cDNA encodes a specific LPA-responsive GPCR with a ligand profile distinct from LPAR1 and LPAR2.
"In this study, we isolated a human cDNA encoding a novel G-protein-coupled receptor, designated EDG7, and characterized it as a cellular receptor for LPA."
-
In recombinant Sf9 cells, unsaturated LPA species activate EDG7-dependent calcium mobilization and potentiate forskolin-driven cAMP accumulation through pertussis-toxin-insensitive signaling.
"Neither the EDG7- nor EDG4-transduced Ca(2+) response or cAMP accumulation was inhibited by pertussis toxin."
-
EDG7 did not mediate LPA-stimulated MAP kinase activation in the tested PC12-cell context.
"In PC12 cells, EDG4 but not EDG2 or EDG7 mediated the activation of MAP kinase by LPA."
Identification of an EDG7 variant, HOFNH30, a G-protein-coupled receptor for lysophosphatidic acid.
-
HOFNH30 is a 354-residue human EDG7-like sequence that the authors proposed could represent a splice variant.
"This receptor has 96% amino acid identity to the Jurkat-T cell-derived EDG7 and could be a splice variant."
-
RT-PCR distinguished placenta expression of HOFNH30 from the highest EDG7 expression in prostate.
"RT-PCR analysis demonstrated that HOFNH30 mRNA is expressed in placenta whereas EDG7 mRNA shows highest expression in prostate."
-
Recombinant HOFNH30 responds to LPA with calcium mobilization and MAPK phosphorylation in RBL-2H3 cells.
"LPA also induced phosphorylation of mitogen-activated protein kinase (p42(MAPK) and p44(MAPK)) in HOFNH30-transfected but not vector-transfected RBL-2H3 cells."
Activity of 2-substituted lysophosphatidic acid (LPA) analogs at LPA receptors: discovery of a LPA1/LPA3 receptor antagonist.
-
Recombinant LPA receptors show sharply different activity profiles for 2-substituted LPA analogs, consistent with a spatially restrictive ligand-binding pocket.
"Analysis of this series at each recombinant LPA receptor using a guanosine 5'-O-(3-[35S]thio)triphosphate (GTP[gamma35S]) binding assay revealed sharp differences in activity."
-
VPC12249 is a competitive antagonist shared by LPAR1 and LPAR3 rather than an LPAR3-selective probe.
"One compound with a bulky hydrophobic group (VPC12249) was a dual LPA1/LPA3 competitive antagonist."
LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing.
-
Targeted deletion of mouse Lpar3 reduces litter size through delayed implantation and altered embryo spacing.
"Targeted deletion of LPA3 in mice resulted in significantly reduced litter size, which could be attributed to delayed implantation and altered embryo spacing."
-
The implantation and spacing defects lead to delayed embryonic development, shared hypertrophic placentas, and embryonic death in the mouse knockout.
"These two events led to delayed embryonic development, hypertrophic placentas shared by multiple embryos and embryonic death."
-
Lpar3-deficient mouse uteri have reduced preimplantation COX2 and the implantation-critical prostaglandins PGE2 and PGI2.
"An enzyme demonstrated to influence implantation, cyclooxygenase 2 (COX2) (ref. 5), was downregulated in LPA3-deficient uteri during pre-implantation. Downregulation of COX2 led to reduced levels of prostaglandins E2 and I2 (PGE2 and PGI2), which are critical for implantation."
-
Prostaglandin replacement rescues implantation timing but not embryo spacing in Lpar3-deficient mice.
"Exogenous administration of PGE2 or carbaprostacyclin (a stable analogue of PGI2) into LPA3-deficient female mice rescued delayed implantation but did not rescue defects in embryo spacing."
Phosphorylation and Internalization of Lysophosphatidic Acid Receptors LPA1, LPA2, and LPA3.
-
Agonist-activated recombinant LPAR3 raises intracellular calcium and undergoes homologous desensitization in C9 cells.
"Agonist-activation increases intracellular calcium concentration in a concentration-dependent fashion."
-
LPA and PKC activation induce phosphorylation and internalization of LPAR3 as well as LPAR1 and LPAR2.
"Lysophosphatidic acid and phorbol myristate acetate were able to induce LPA1-3 phosphorylation, in time- and concentration-dependent fashions. It was also clearly observed that agonists and protein kinase C activation induced internalization of these receptors."
-
LPA-receptor-driven ERK activation in this system depends substantially on EGFR transactivation.
"Activation of LPA1-3 receptors induced ERK 1/2 phosphorylation; this effect was markedly attenuated by inhibition of epidermal growth factor receptor tyrosine kinase activity, suggesting growth factor receptor transactivation in this effect."
A reference map of the human binary protein interactome.
-
HuRI interaction candidates were generated by systematic yeast two-hybrid screening, pairwise retesting, and sequence confirmation rather than targeted LPAR3 mechanistic experiments.
"To map the reference interactome, we performed nine screens of Space III, followed by pairwise verification by quadruplicate retesting and sequence confirmation."
-
Most HuRI interactions were recovered in only one screen, so individual LPAR3 partners remain screen-level candidates without context-specific functional validation.
"These results reinforce previous observations12,22 that the protein interactome might be dominated by weaker and more transient PPIs that are difficult to detect, as indicated by the fact that the majority of PPIs in HuRI were found in only one screen (Extended Data Fig. 3h, i)."
The LPA(3) Receptor: Regulation and Activation of Signaling Pathways.
-
The review synthesizes LPAR3 as coupling mainly to Gαq/11 and Gαi/o while emphasizing that regulation and trafficking were poorly resolved at the time.
"The LPA3 receptor is a GPCR whose activation mainly promotes the recruitment of two G proteins: Gαq/11 and Gαi/o; therefore, it is considered promiscuous."
-
The review explicitly cautions that then-current models of LPAR3 phosphorylation-dependent trafficking were largely hypothetical.
"Similarly, the LPA3 receptor internalization process is essentially unexplored. Therefore, we have to assume that the molecular consequences of phosphorylation in signaling and intracellular location/trafficking are similar to those observed for other receptors."
LPA(3) Receptor Phosphorylation Sites: Roles in Signaling and Internalization.
-
Mutating phosphorylation sites in both intracellular loop 3 and the C-terminal tail nearly abolishes LPAR3 phosphorylation.
"Agonist- and LPA-mediated receptor phosphorylation was diminished in the IL3 and Ctail mutants and essentially abolished in the IL3/Ctail mutant, confirming that the main phosphorylation sites are present in both domains and their role in receptor phosphorylation eliminated by substitution and distributed in both domains."
-
These phosphorylation-site mutations strongly impair β-arrestin-2 recruitment and LPAR3 internalization.
"LPA and PMA-induced receptor interaction with β-arrestin 2 and LPA3 internalization were severely diminished in cells expressing the mutants."
Lysophosphatidic Acid Receptor 3 (LPA3): Signaling and Phosphorylation Sites.
-
LPA stimulates pertussis-toxin-insensitive calcium mobilization and ERK phosphorylation through recombinant LPAR3.
"The agonist, lysophosphatidic acid (LPA), increased intracellular calcium and ERK phosphorylation through pertussis toxin-insensitive processes."
-
LPA drives rapid β-arrestin association and clathrin-sensitive internalization of LPAR3.
"Pitstop 2 (clathrin heavy chain inhibitor) markedly reduced LPA-induced receptor internalization; in contrast, phorbol ester-induced internalization was only delayed. LPA induced rapid β-arrestin-LPA3 receptor association."
-
Mass spectrometry maps LPAR3 phosphorylation to residues in intracellular loop 3 and the C-terminal tail.
"Phosphorylated residues were detected in the intracellular loop 3 (S221, T224, S225, and S229) and in the carboxyl terminus (S321, S325, S331, T333, S335, Y337, and S343)."
Liganded Gq/11-activating GPCRs act as GEFs for Gq/11
Liganded Gi-activating GPCR acts as a GEF for Gi
LPA-binding receptors bind LPA
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
Molecular cloning and characterization of a lysophosphatidic acid receptor, Edg-7, expressed in prostate.
Vascular smooth muscle migration and proliferation in response to lysophosphatidic acid (LPA) is mediated by LPA receptors coupling to Gq.
Expression and function of lysophosphatidic acid receptors in cultured rodent microglial cells.
Altered spatiotemporal expression of collagen types I, III, IV, and VI in Lpar3-deficient peri-implantation mouse uterus.
Lysophosphatidic acid induces neurite branch formation through LPA3.