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
G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth.
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Human P2RY5/LPAR6 was identified as an LPA-responsive GPCR through reporter-gene and radioligand-binding experiments.
"Furthermore, we identified oleoyl-L-alpha-lysophosphatidic acid (LPA), a bioactive lipid, as a ligand for P2Y5 in reporter gene and radioligand binding experiments."
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Homozygous truncating P2RY5 variants segregated with autosomal recessive hypotrichosis, linking the receptor to maintenance of human hair growth.
"We mapped an autosomal recessive form of this disorder to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5, which encodes an orphan G protein-coupled receptor."
Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair.
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Pathogenic P2RY5 variants were found in six linked families with autosomal recessive woolly hair.
"In all cases, we discovered pathogenic mutations in P2RY5, which encodes a G protein-coupled receptor and is a nested gene residing within intron 17 of the retinoblastoma 1 (RB1) gene."
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P2RY5 is expressed in the Henle and Huxley layers of the human hair-follicle inner root sheath.
"P2RY5 is expressed in both Henle's and Huxley's layers of the inner root sheath of the hair follicle."
Identification and characterization of a novel lysophosphatidic acid receptor, p2y5/LPA6.
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Human p2y5 was functionally identified as LPA6 and coupled to G13-Rho signaling in heterologous receptor-null cell assays.
"Here we report that p2y5 is a novel LPA receptor coupling to the G13-Rho signaling pathway."
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Endogenous p2y5 contributed to LPA-induced contraction in human umbilical-vein endothelial cells.
"LPA-induced contraction of human umbilical vein endothelial cells was suppressed by small interfering RNA knockdown of endogenously expressed p2y5."
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LPAR6 responded more strongly to 2-acyl-LPA than to 1-acyl-LPA.
"We also found that 2-acyl-LPA had higher activity to p2y5 than 1-acyl-LPA."
P2Y5 is a G(alpha)i, G(alpha)12/13 G protein-coupled receptor activated by lysophosphatidic acid that reduces intestinal cell adhesion.
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LPA activation of heterologously expressed P2Y5 engaged Gi-sensitive calcium and ERK signaling.
"Together these indicate that P2Y5 activation by LPA induces an increase in [Ca(2+)](i) and ERK1/2 phosphorylation through G(alpha)(i)."
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LPA- or FPP-activated P2Y5 engaged a G12/13-Rho-ROCK-sensitive reporter pathway.
"The activation of P2Y5 by LPA or FPP induced the activity of a serum response element (SRE)-linked luciferase reporter that was inhibited by the RGS domain of p115RhoGEF, C3 exotoxin, and Y-27632, suggesting the involvement of G(alpha)(12/13), Rho GTPase, and ROCK, respectively."
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LPA, but not FPP, activation of P2Y5 reduced adhesion in the intestinal-cell model.
"These observations correlate with our subsequent finding that P2Y5 activation by LPA, and not FPP, reduced intestinal cell adhesion."
A reference map of the human binary protein interactome.
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HuRI is a large systematic map of human binary protein interactions rather than a targeted LPAR6 mechanistic study.
"Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'."
Cell-trafficking impairment in disease-associated LPA6 missense mutants and a potential pharmacoperone therapy for autosomal recessive woolly hair/hypotrichosis.
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Eight of nine tested disease-associated LPA6 missense variants were loss-of-function in exogenous LPA-response assays.
"In our exogenous expression experiments, all mutants except S3T failed to respond to LPA, indicating that they are loss-of-function mutants."
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Five disease-associated LPA6 variants had reduced cell-surface expression because of ER retention.
"Among the nine mutants, five (D63V, G146R, N246D, L277P and C278Y) displayed impaired expression at the cell surface because of endoplasmic reticulum (ER) retention, indicating that these mutants are trafficking-defective, as reported in other disease-associated GPCRs."
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Alkyl-OMPT rescued surface expression of D63V and N246D, and the rescued N246D receptor was functional.
"Notably, alkyl-OMPT, a potent synthetic agonist for LPA6 restored the defective cell surface expression of two of the ER-retained mutants, D63V and N246D, possibly by its chaperoning function that allows them to escape intracellular retention as well as proteasomal degradation. Furthermore, the alkyl-OMPT-rescued N246D mutant was shown be functional."
Molecular mechanism of ligand recognition and activation of lysophosphatidic acid receptor LPAR6.
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Cryo-EM resolved LPA-bound human LPAR6 complexes with mini-G13 and mini-Gq, with stronger functional coupling to G13.
"We resolved the structures of the LPA-bound LPAR6/G13 and LPA-bound LPAR6/Gq complexes at resolutions of 3.06 Å and 2.89 Å, respectively, using single particle cryo-EM analysis"
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Mutagenesis validated key polar LPAR6 residues that recognize the LPA headgroup and glycerol moiety.
"Mutants R256A6.62, Y252A6.58, and W177A5.31, which disrupt polar interactions with the phosphate head of LPA, largely decrease receptor activity"
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The structure and BRET mutagenesis distinguish G13- and Gq-selective receptor contacts.
"These mutant data corroborate our structural observations regarding LPAR6’s coupling with Gq and G13."
Liganded Gq/11-activating GPCRs act as GEFs for Gq/11
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Reactome places LPAR6 in the generic proximal Gq/11 activation reaction.
"G alpha q protein (or Gq/11) consists of four family members (G-alpha 11, -alpha 14, -alpha 15 and -alpha q)."
P2Y5 receptor can bind to LPA
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Reactome records LPA binding by P2Y5/LPAR6 and coupling to Gq/11 and G12/13.
"The P2Y5 receptor (Lee CW et al, 2006) binds lysophosphatidic acid (LPA). Its effects are mediated by coupling with the G protein alpha G q/11 and G12/13 subunits (Lee CW et al, 2006)."
Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq
The Ligand:GPCR:Gq complex dissociates