LPAR6, historically called P2Y5/P2RY5, is a class-A seven-transmembrane G protein-coupled receptor that recognizes extracellular lysophosphatidic acid at the plasma membrane. Human LPAR6 expressed in receptor-null rodent cells responds preferentially to 2-acyl-LPA over 1-acyl-LPA and most consistently activates a G12/13-Rho pathway; Gi-dependent calcium and ERK responses and Gq coupling are also supported in defined heterologous systems. Knockdown of endogenous LPAR6 suppresses LPA-induced contraction of human endothelial cells, providing a bounded native-human link to the recombinant signaling results. Cryo-EM structures of engineered, LPA-bound human LPAR6 with mini-G13 or mini-Gq define the ligand pocket and distinct coupling contacts, with functional mutagenesis supporting both interfaces and stronger G13 coupling. These structures represent activated signaling states rather than constitutive stable complexes. LPAR6 is expressed in human skin and hair follicles, including Henle and Huxley layers of the inner root sheath. Biallelic loss-of-function variants cause autosomal recessive woolly hair and hypotrichosis, establishing an essential role in hair growth and texture. Several disease-associated missense forms are retained in the endoplasmic reticulum and fail to reach the cell surface, whereas other surface-expressed variants are signaling defective; these are allelic forms, not protein isoforms. Variant-specific rescue by the synthetic agonist alkyl-OMPT and activation by farnesyl pyrophosphate have been observed in expression systems but do not establish general clinical rescue or an alternative endogenous human ligand.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted as the core plasma-membrane location of LPAR6. Reason: LPAR6 is an integral seven-transmembrane LPA receptor whose human receptor activity and signaling occur at the plasma membrane; independent experimental localization and trafficking evidence agree with the phylogenetic inference. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1298208 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. MGI:MGI:1925384 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. MGI:MGI:1929509 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. PANTHER:PTN000660850 SUPPORTS TRANSFER Exact WITH/FROM phylogenetic node supporting the conserved receptor location. RGD:2586 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:P25116 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:P43657 SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own EXP/IDA/TAS annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. UniProtKB:P46093 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:P55085 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:Q86VZ1 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:Q8IYL9 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:Q96RI0 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:Q99677 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:Q99678 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:Q9BXC1 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:Q9HC97 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. UniProtKB:Q9Y2T6 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. ZFIN:ZDB-GENE-061013-343 SUPPORTS TRANSFER Exact WITH/FROM source; it supports conserved plasma-membrane localization in the receptor family. |
| GO:0007186 G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted as the core signaling process initiated by ligand-bound LPAR6. Reason: LPAR6 is a bona fide LPA-responsive GPCR, established by ligand-binding and signal-transduction assays in PMID:18297070. The broad pathway term is therefore valid, although it does not specify the proximal G-protein branch. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:101802 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. MGI:MGI:101910 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. MGI:MGI:1298208 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. MGI:MGI:2441992 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. PANTHER:PTN000660850 SUPPORTS TRANSFER Exact WITH/FROM phylogenetic node supporting conserved receptor signaling. RGD:2586 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. UniProtKB:P25116 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. UniProtKB:P46093 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. UniProtKB:P55085 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. UniProtKB:Q86VZ1 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. UniProtKB:Q8IYL9 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. UniProtKB:Q9HC97 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. UniProtKB:Q9Y2T6 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. ZFIN:ZDB-GENE-061013-343 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. ZFIN:ZDB-GENE-101202-1 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved GPCR signaling. |
| GO:0070915 lysophosphatidic acid receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted as the ligand-specific core molecular function of LPAR6. Reason: Oleoyl-L-alpha-lysophosphatidic acid was identified as an LPAR6/P2Y5 ligand by reporter and radioligand-binding experiments in PMID:18297070, directly supporting the receptor-specific term. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002796574 SUPPORTS TRANSFER Exact WITH/FROM phylogenetic node supporting ligand-specific LPA receptor activity. ZFIN:ZDB-GENE-061013-343 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved LPA receptor activity. ZFIN:ZDB-GENE-110408-67 SUPPORTS TRANSFER Exact WITH/FROM source supporting conserved LPA receptor activity. |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: The generic GPCR activity is valid but should be represented by the established ligand-specific receptor activity. Reason: The rhodopsin-like GPCR family mapping correctly identifies receptor activity, but direct human ligand-binding and signaling evidence supports the more informative lysophosphatidic acid receptor activity term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR000276 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the broad GPCR concept, while direct LPAR6 evidence supports the more precise replacement. Proposed replacements: lysophosphatidic acid receptor activity |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accepted as the core cell-surface location of LPAR6. Reason: The UniProt subcellular-location mapping agrees with experimental plasma-membrane localization and with the cell-surface trafficking behavior of wild-type LPAR6 reported in PMID:36173926. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated location agrees with independent human LPAR6 evidence. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Accepted as the core signaling process initiated by LPA-bound LPAR6. Reason: The rhodopsin-like GPCR family mapping is concordant with direct human evidence that LPA activates LPAR6-dependent reporter and signal-transduction responses. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000276 SUPPORTS TRANSFER Exact WITH/FROM source; the family-based process assignment agrees with established human LPAR6 signaling. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The generic membrane term should be replaced by the established plasma-membrane location. Reason: The transmembrane-family mapping is correct but underspecified. Independent experimental localization and cell-surface trafficking evidence support plasma membrane as the informative location. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR000276 SUPPORTS TRANSFER Exact WITH/FROM source; it supports membrane localization, while human evidence supports the more precise replacement. InterPro:IPR017452 SUPPORTS TRANSFER Exact WITH/FROM source; it supports membrane localization, while human evidence supports the more precise replacement. Proposed replacements: plasma membrane |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Marked as over-annotated because generic protein binding from a binary-interactome screen does not define an informative LPAR6 molecular function. Reason: PMID:32296183 is a large-scale binary interaction map. The four recovered partners are preserved as exact provenance, but the screen does not establish a shared mechanistic interaction, a stable physiological complex, or a more specific binding activity for LPAR6; generic protein binding is therefore uninformative. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Accepted as direct antibody-based evidence for plasma-membrane localization. Reason: The Human Protein Atlas immunofluorescence curation assigns LPAR6 to the plasma membrane, consistent with its multi-pass receptor topology and with independent cell-surface localization evidence. |
| GO:0005886 plasma membrane | EXP PMID:36173926 Cell-trafficking impairment in disease-associated LPA6 misse... | ACCEPT | Summary: Accepted as experimental evidence that wild-type LPAR6 reaches the plasma membrane. Reason: PMID:36173926 reports exogenous-expression experiments in which disease-associated mutants showed impaired cell-surface expression and ER retention relative to functional wild-type LPAR6. This directly supports plasma-membrane localization of the wild-type receptor, while the trafficking defects are variant-specific. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379048 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal Gq/11 signaling. Reason: Reactome places liganded LPAR6 among plasma-membrane GPCRs acting as GEFs for Gq/11. This pathway placement is consistent with receptor topology and direct human LPA-responsive signaling evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-417890 | ACCEPT | Summary: Accepted as the plasma-membrane location of the LPA-binding receptor event. Reason: Reactome places P2Y5/LPAR6 at the plasma membrane when it binds LPA. This is directly concordant with the ligand-binding and signaling experiments reported in PMID:18297070. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: Accepted as the plasma-membrane location of the curated receptor-Gq association step. Reason: Reactome places liganded LPAR6 at the plasma membrane during binding of inactive heterotrimeric Gq. The localization is compatible with the receptor's multi-pass topology and experimentally supported cell-surface localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: Accepted as the plasma-membrane location of the curated receptor-Gq dissociation step. Reason: Reactome locates LPAR6 at the plasma membrane when the activated ligand-receptor-Gq complex dissociates. This is consistent with experimental plasma-membrane localization of the receptor. |
| GO:0005886 plasma membrane | IDA PMID:18297070 G protein-coupled receptor P2Y5 and its ligand LPA are invol... | ACCEPT | Summary: Accepted with curator deference as direct plasma-membrane localization evidence. Reason: The cached record is abstract-only and does not expose the localization experiment, so the experimental curator assignment should not be overruled. Plasma-membrane localization is biologically coherent with the paper's characterization of P2Y5/LPAR6 as an LPA-responsive GPCR and with independent cell-surface evidence from PMID:36173926. |
| GO:0035025 positive regulation of Rho protein signal transduction | IDA PMID:19386608 Identification and characterization of a novel lysophosphati... | NEW | Summary: Proposed as a new annotation for the directly demonstrated G13-Rho branch of LPAR6 signaling. Reason: Human LPAR6 expressed in receptor-null cells activates G13-Rho signaling, and an independent study places G12/13, Rho, and ROCK downstream of LPA-activated LPAR6. These assays establish proximal positive regulation of Rho signaling while not transferring model-specific contraction or adhesion phenotypes to all human tissues. Supporting Evidence: PMID:19386608 Here we report that p2y5 is a novel LPA receptor coupling to the G13-Rho signaling pathway. |
| GO:0001942 hair follicle development | IMP PMID:18297070 G protein-coupled receptor P2Y5 and its ligand LPA are invol... | NEW | Summary: Proposed as a new non-core annotation for the human hair-follicle process established by biallelic LPAR6 loss of function. Reason: Independent human families with biallelic truncating or pathogenic LPAR6 variants show autosomal recessive woolly hair and hypotrichosis, and LPAR6 is expressed in the inner root sheath. This supports involvement in hair follicle development while keeping the developmental phenotype distinct from the receptor's core molecular activity. Supporting Evidence: PMID:18297070 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. |
Loading supporting content…
Download this section (compressed HTML)Q: What are the endogenous G12/13, Gq, Gi/o, and beta-arrestin coupling weights of human LPAR6 in inner-root-sheath, epidermal, and endothelial cells?
Q: Which 1-acyl- and 2-acyl-LPA species occupy LPAR6 in native human tissues, and is FPP physiologically relevant to the receptor?
Q: Which LPAR6-dependent branch and downstream effectors maintain human hair-shaft growth and texture?
Q: Which disease-associated LPAR6 alleles fail by misfolding, defective export, ligand recognition, or G-protein coupling, and which can be rescued safely?
Q: Are any endogenous LPAR6 protein isoforms or stable regulatory partners functionally distinct?
Experiment: Endogenously tag or minimally modify LPAR6 in human inner-root-sheath, epidermal, and endothelial models, then measure G12/13, Gq, Gi/o, beta-arrestin, Rho, calcium, ERK, and cyclic-nucleotide responses to matched 1-acyl- and 2-acyl-LPA panels with G-alpha knockout and genomic rescue controls.
Hypothesis: Native human LPAR6 favors G12/13-G13 signaling, while the relative Gi and Gq contributions vary by cell type and LPA species.
Type: endogenous coupling and ligand-bias profiling
Experiment: Quantify extracellular and membrane LPA species in microdissected follicular compartments, then combine LPAR6 knockout/rescue with stabilized ligand competition and branch-resolved signaling measurements in follicle organoids.
Hypothesis: Local enrichment of 2-acyl-LPA drives preferential LPAR6 activation in the human hair-follicle compartment.
Type: native ligand lipidomics and receptor occupancy
Experiment: Build human follicle organoids with lineage-restricted LPAR6 knockout and rescue, perturb G12/13, Rho, Gi, and Gq branches independently, and quantify sheath-cell mechanics, shaft curvature, growth, and differentiation over time.
Hypothesis: LPAR6-G12/13-Rho signaling in inner-root-sheath cells is required for normal hair-shaft morphogenesis.
Type: human follicle signaling epistasis
Experiment: Introduce representative patient alleles at the endogenous locus in follicular cells and measure folding, ER retention, surface delivery, degradation, ligand occupancy, and G-protein coupling before and after alkyl-OMPT or matched pharmacological-chaperone treatment.
Hypothesis: Trafficking-defective and surface-expressed signaling-defective LPAR6 alleles require distinct rescue strategies.
Type: endogenous variant mechanism and rescue stratification
Experiment: Perform endogenous LPAR6 proximity labeling in follicular and endothelial cells, test overlap with EMP1, SEC22A, SMIM3, and RPRM, and require reciprocal interaction, colocalization, perturbation, and rescue before assigning a stable regulatory relationship.
Hypothesis: A subset of screen-derived LPAR6 partners reproducibly regulates receptor trafficking or signaling in a native-expression context.
Type: endogenous partner validation
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The quantitative G12/13, Gq, Gi/o, and beta-arrestin coupling profile of endogenous human LPAR6 is unresolved across native cell types.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: G13-Rho is supported by multiple recombinant studies and a human endothelial knockdown phenotype, while Gi and Gq are supported in defined heterologous or engineered systems. Cryo-EM resolves mini-G13 and mini-Gq interfaces but does not measure coupling weights in native hair-follicle cells.
Significance: Native branch selection is likely to determine how the same receptor controls hair-follicle architecture and other tissue-specific responses.
What would resolve it: Measure endogenous LPAR6 with parallel G12/13, Gq, Gi/o, beta-arrestin, Rho, calcium, ERK, and cyclic-nucleotide biosensors in human inner-root-sheath, epidermal, and endothelial models.
Gap: The endogenous LPA molecular species that occupy LPAR6 in human tissues and the physiological significance of its reported 2-acyl-LPA preference are unknown.
OPEN BIOLOGY
What is known: Recombinant assays show greater activity of 2-acyl- than 1-acyl-LPA, whereas the structural preparations used 1-acyl-LPA because 2-acyl-LPA is unstable. FPP can activate LPAR6 in heterologous assays but is not established as an endogenous human LPAR6 ligand.
Significance: Local ligand composition could control receptor occupancy, potency, and branch bias in the hair follicle and vascular compartments.
What would resolve it: Combine extracellular and membrane lipidomics with endogenous LPAR6 knockout, genomic rescue, and branch-resolved dose-response measurements using stabilized 1-acyl- and 2-acyl-LPA species.
Gap: The proximal LPAR6 signaling branch and downstream effectors that maintain human hair-shaft growth and texture are not defined.
OPEN BIOLOGY
What is known: Human biallelic loss-of-function genetics and inner-root-sheath expression establish the follicular requirement, but most coupling experiments used receptor-null rodent or other heterologous cells rather than native human follicular cells.
Significance: Resolving the cell type and signaling branch would connect the receptor's core molecular activity to the human phenotype without transferring model-specific adhesion or contraction outputs.
What would resolve it: Perturb endogenous LPAR6 and individual G-protein branches in human follicle organoids containing Henle and Huxley lineages, with rescue by wild-type receptor and quantitative hair-shaft morphogenesis readouts.
Gap: Why different disease-associated LPAR6 missense variants cause trafficking failure versus surface-expressed signaling failure, and which defects are pharmacologically rescuable, remains incompletely resolved.
OPEN BIOLOGY
What is known: Five tested variants showed ER retention and impaired surface expression, while several other loss-of-function variants reached the surface. Alkyl-OMPT rescued surface expression of only D63V and N246D in an exogenous system, and clinical efficacy has not been established.
Significance: Mechanistic stratification is required before genotype-specific rescue can be evaluated as a therapeutic strategy.
What would resolve it: Compare folding, export, degradation, ligand binding, coupling, and rescue across a complete variant panel in endogenously expressed human follicular models.
Gap: Functionally distinct endogenous LPAR6 protein isoforms and stable receptor-specific interaction partners have not been established.
OPEN BIOLOGYCURATION
What is known: Multiple transcript accessions do not demonstrate distinct protein isoforms. Disease-tested sequences are allelic variants, the cryo-EM receptor-G-protein assemblies are activated states, and the four HuRI pairs are screen-level binary detections without targeted physiological validation.
Significance: Unsupported isoform or complex claims could misattribute tissue-specific trafficking and signaling mechanisms.
What would resolve it: Reconcile full-length transcripts by long-read sequencing and proteomics, and test endogenous proximity-labeling candidates by reciprocal interaction, colocalization, and genetic epistasis assays.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)