Affinage

MRGPRF

Mas-related G-protein coupled receptor member F · UniProt Q96AM1

Length
343 aa
Mass
38.2 kDa
Annotated
2026-06-10
19 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MRGPRF (GPR168/MrgprF) is an orphan Mas-related GPCR that acts as a tumor suppressor in cutaneous melanoma, where it reduces assembly of the PI3K p101/p110γ complex, limiting PIP2-to-PIP3 conversion and dampening downstream PI3K/Akt signaling; forced expression curbs proliferation, migration, and xenograft growth while knockdown is pro-tumorigenic, and the phenotype is reversed by the Akt agonist SC79 (PMID:35504869). This anti-proliferative output is mediated through receptor functionality, as a blocking anti-GPR168 antibody restores melanoma proliferation and the Akt/GSK-3β/β-catenin/Myc/CyclinD1/CDK4 axis (PMID:38805406). MRGPRF protein abundance is set post-translationally by USP45, which binds the receptor N-terminus through its catalytic domain and removes K63-linked ubiquitin chains to stabilize the protein, establishing a USP45→MRGPRF deubiquitination-dependent tumor-suppressor axis (PMID:40788071). In the nervous system MRGPRF modulates somatosensation: global knockout reduces thermal and chemical nociceptive responses and downregulates DRG nociceptive genes including Nav1.7/1.8/1.9, c-fos, and Runx1 (PMID:40033362), and its dorsal-horn protein level—and consequent itch sensitivity—is governed by gut-microbiota-driven RNA m6A methylation acting through an ETS1/FTO axis (PMID:40289281). The receptor shows restricted peripheral expression in entero-endocrine cells of human ileum and colon (PMID:37314493) and in enteric neuronal subpopulations whose numbers fall during intestinal inflammation (PMID:21912971). A defined endogenous ligand has not been identified in the available corpus, and heterologous dog MRGPRF does not mediate histamine-releasing or fluoroquinolone-induced calcium signaling (PMID:32999394).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2008 Low

    First hint of regulatory wiring around MRGPRF in sensory neurons came from observing that loss of a related Mrg receptor selectively elevates MrgF, raising the question of how Mrg-family members cross-regulate.

    Evidence MrgE knockout mice with DRG gene expression profiling

    PMID:18197975

    Open questions at the time
    • single correlative expression observation with no mechanistic follow-up on MRGPRF
    • no causal link between MrgE loss and MrgF regulation established
    • no functional consequence tested
  2. 2011 Medium

    Established where MRGPRF acts in the gut and that its expression is dynamically controlled, showing it marks enteric neuronal subtypes whose numbers decline under inflammation.

    Evidence RT-PCR, qPCR, and IHC on murine ileum in schistosomiasis and chemical ileitis models

    PMID:21912971

    Open questions at the time
    • mechanism linking inflammation to MrgF downregulation unknown
    • functional role of MrgF in enteric neurons not tested
    • no ligand or signaling readout
  3. 2020 Medium

    Addressed whether MRGPRF mediates the pseudo-allergic responses typical of its family, finding it does not signal to calcium in response to histamine-releasing agents, narrowing its candidate functions.

    Evidence Intracellular Ca2+ mobilization assay in HEK293 cells transfected with dog MRGPRF versus MRGPRX2

    PMID:32999394

    Open questions at the time
    • negative result does not identify the true ligand or coupling
    • tested only dog ortholog in a heterologous system
    • did not survey other second messengers
  4. 2022 High

    Defined MRGPRF's first concrete molecular function: a melanoma tumor suppressor that blocks PI3K complex assembly and Akt signaling, answering what cellular process the receptor controls.

    Evidence Reciprocal overexpression/knockdown in melanoma lines, PI3K subunit Co-IP, Akt-agonist (SC79) epistasis rescue, and xenografts

    PMID:35504869

    Open questions at the time
    • how a GPCR mechanistically reduces p101/p110γ assembly is unresolved
    • no endogenous ligand linking receptor activation to PI3K inhibition
    • G-protein coupling not defined
  5. 2024 Medium

    Confirmed that MRGPRF's anti-tumor effect requires intact receptor function and traced its output through the Akt/β-catenin/cell-cycle axis.

    Evidence GPR168 overexpression in B16-F10 cells, xenografts, western blot of pathway components, and blocking anti-GPR168 antibody rescue

    PMID:38805406

    Open questions at the time
    • antibody blockade does not identify the natural agonist
    • single lab
    • does not connect to the PI3K complex mechanism biochemically
  6. 2025 High

    Identified the upstream control of MRGPRF protein stability, showing USP45 deubiquitinates K63 chains on the receptor N-terminus to maintain its tumor-suppressor levels.

    Evidence USP screen, Co-IP/pulldown, domain mapping, K63-linkage ubiquitination assays, and MRGPRF-rescue epistasis with xenografts

    PMID:40788071

    Open questions at the time
    • E3 ligase placing K63 chains on MRGPRF unknown
    • whether deubiquitination alters trafficking versus degradation not resolved
    • USP45-MRGPRF axis tested only in melanoma
  7. 2025 Medium

    Demonstrated MRGPRF's causal role in somatosensation, with knockout blunting nociception and a gut-microbiota/m6A pathway tuning its dorsal-horn levels to set itch sensitivity.

    Evidence MrgF global knockout with behavioral nociception tests and DRG qPCR; germ-free/antibiotic mice, m6A mapping, ETS1/FTO analysis, and metabolite (ALC) rescue

    PMID:40033362 PMID:40289281

    Open questions at the time
    • signaling mechanism by which MRGPRF modulates neuronal excitability unknown
    • ligand activating MRGPRF in DRG/dorsal horn not identified
    • link between m6A pathway and behavior is correlative across tissues
  8. 2023 Low

    Extended MRGPRF function beyond tumor and nerve to metabolic tissue, indicating it supports adipocyte viability and regulates cAMP.

    Evidence GPCRome screen of adipose tissue with knockdown/overexpression in a (pre)adipocyte model and cAMP measurement

    PMID:37766984

    Open questions at the time
    • minimal methodological detail and no mutagenesis or reconstitution
    • G-protein coupling to cAMP not directly demonstrated
    • single lab, not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous ligand and G-protein coupling of MRGPRF remain unknown, leaving open how receptor activation is mechanistically transduced into PI3K suppression, cAMP regulation, and neuronal modulation.
  • no endogenous agonist identified
  • G-protein/second-messenger coupling undefined
  • structural basis of signaling unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
USP45

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 MrgprF reduces PI3K complex formation between p101 and p110γ subunits, thereby inhibiting the critical step of PIP2-to-PIP3 conversion and suppressing downstream PI3K/Akt signaling in cutaneous melanoma cells. Forced expression inhibits tumor cell proliferation, migration, xenograft growth, and metastasis; knockdown promotes proliferation and transformation. The Akt-specific agonist SC79 reverses these effects. Forced expression and knockdown in melanoma cell lines; xenograft tumor models; co-immunoprecipitation/pulldown of PI3K subunits; rescue with Akt agonist SC79; in vitro and in vivo functional assays Signal transduction and targeted therapy High 35504869
2024 GPR168 (MRGPRF) overexpression in mouse melanoma B16-F10 cells inhibits proliferation and migration through the Akt signaling pathway, evidenced by decreased p-Akt, p-GSK-3β, β-catenin, Myc, CyclinD1, and CDK4. A blocking anti-GPR168 polyclonal antibody restores proliferation and migration, confirming that signaling depends on GPR168 receptor functionality. GPR168 overexpression in B16-F10 cells; xenograft tumor model; western blot for pathway components; rescue with anti-GPR168 blocking antibody PloS one Medium 38805406
2025 USP45 directly binds the N-terminal domain of MRGPRF via its catalytic domain and stabilizes MRGPRF protein by removing K63-linked ubiquitination. USP45 knockdown destabilizes MRGPRF and promotes melanoma cell malignancy; these effects are rescued by MRGPRF overexpression, placing USP45 upstream of MRGPRF in a deubiquitination-dependent tumor suppressor axis. Screening of 40 USPs; Co-IP and pulldown of USP45-MRGPRF interaction; domain mapping (N-terminal MRGPRF); ubiquitination assays (K63-linkage); USP45 OE/KD functional assays; MRGPRF depletion/rescue epistasis; xenograft mouse model Advanced science High 40788071
2025 In the mouse spinal cord, MrgprF (MRGPRF) protein levels are regulated by RNA m6A methylation of MrgprF mRNA. Gut microbiota depletion reduces expression of the m6A demethylase FTO (via inactivation of the transcription factor ETS1 at the Fto promoter), leading to increased m6A methylation on MrgprF mRNA and decreased MRGPRF protein in the dorsal horn, resulting in reduced itch sensation. Oral administration of acetyl-L-carnitine (ALC) from Bacteroides fragilis restores FTO and MRGPRF levels. Antibiotic-treated and germ-free mouse models; oral gavage with B. fragilis and ALC; m6A site mapping on MrgprF mRNA; FTO expression analysis; ETS1 chromatin binding at Fto promoter; behavioral itch assays Gut microbes Medium 40289281
2025 Global knockout of MrgF (MRGPRF) in mice reduces pain-related behavioral responses to thermal and chemical (formalin) nociceptive stimuli, without affecting motor coordination or cerebellar histology. In MrgF-/- DRG, expression of nociceptive modulation genes c-fos, Runx1, Nav1.7, Nav1.8, and Nav1.9 is downregulated, placing MrgF in a pathway that modulates pain sensitivity. MrgF global knockout mouse model; behavioral tests (hot plate, tail flick, formalin, rotarod, pole, balance beam, treadmill); qPCR for nociceptive genes in DRG; cerebellar histology Hereditas Medium 40033362
2011 MrgF (MRGPRF) is expressed in distinct enteric neuronal subpopulations in the murine ileum, including sensory, secretomotor, and vasodilator neurons, and in nerve fibers of the tunica muscularis and lamina propria. The number of MrgF-expressing enteric neurons is significantly reduced during intestinal schistosomiasis and chemically induced ileitis, indicating that inflammation negatively regulates MrgF expression in the enteric nervous system. RT-PCR, quantitative PCR, and immunohistochemistry on murine ileum from control, schistosomiasis, and chemically induced ileitis models Histochemistry and cell biology Medium 21912971
2008 Deletion of MrgE in mice results in upregulation of MrgF (MRGPRF) expression in DRG as the sole significantly affected Mrg family member, suggesting a regulatory relationship between MrgE and MrgF expression. MrgE knockout mice; gene expression analysis of Mrg family members and 84 sensory neuron genes in DRG Molecular pain Low 18197975
2023 MRGPRF is essential for adipocyte viability and regulates intracellular cAMP levels in a (pre)adipocyte cell model, as determined by functional knockdown/overexpression experiments in the context of a GPCRome screen of adipose tissue. RNA-seq database (FATTLAS); functional assays in (pre)adipocyte cell model with MRGPRF manipulation; cAMP level measurement iScience Low 37766984
2023 MRGPRF protein is specifically expressed by entero-endocrine cells (EECs) in the mucosal biopsies of human terminal ileum and sigmoid colon, making it the only detectable MRGPR family member at these mucosal sites. RT-PCR on human GI mucosal biopsies; immunohistochemical staining for cell-type identification Cell and tissue research Medium 37314493
2020 In functional calcium mobilization assays, HEK293 cells transfected with dog MRGPRF did not respond to histamine-releasing agents (including fluoroquinolones), in contrast to dog or human MRGPRX2, indicating that MRGPRF does not mediate drug-induced pseudo-allergic calcium signaling in this heterologous expression system. Intracellular Ca2+ mobilization assay in HEK293 cells transiently transfected with dog MRGPRF; comparison with MRGPRX2, MRGPRD, MRGPRG Scientific reports Medium 32999394

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Comprehensive genome and transcriptome analysis of the 11q13 amplicon in human oral cancer and synteny to the 7F5 amplicon in murine oral carcinoma. Genes, chromosomes & cancer 111 16906560
2020 Identification of novel methylation markers in HPV-associated oropharyngeal cancer: genome-wide discovery, tissue verification and validation testing in ctDNA. Oncogene 51 32415241
2022 MrgprF acts as a tumor suppressor in cutaneous melanoma by restraining PI3K/Akt signaling. Signal transduction and targeted therapy 42 35504869
2013 An mRNA atlas of G protein-coupled receptor expression during primary human monocyte/macrophage differentiation and lipopolysaccharide-mediated activation identifies targetable candidate regulators of inflammation. Immunobiology 39 23948647
2011 The effect of inflammation on the expression and distribution of the MAS-related gene receptors MrgE and MrgF in the murine ileum. Histochemistry and cell biology 26 21912971
2023 lnc-MRGPRF-6:1 Promotes ox-LDL-Induced Macrophage Ferroptosis via Suppressing GPX4. Mediators of inflammation 24 37621767
2010 Epigenetic modification of retinoic acid-treated human embryonic stem cells. BMB reports 23 21189161
2022 Epigenetic study of early breast cancer (EBC) based on DNA methylation and gene integration analysis. Scientific reports 22 35132081
2022 Gemcitabine combined with apatinib and toripalimab in recurrent or metastatic nasopharyngeal carcinoma. Med (New York, N.Y.) 20 36041429
2022 lnc-MRGPRF-6:1 Promotes M1 Polarization of Macrophage and Inflammatory Response through the TLR4-MyD88-MAPK Pathway. Mediators of inflammation 18 35125964
2020 Identification of the dog orthologue of human MAS-related G protein coupled receptor X2 (MRGPRX2) essential for drug-induced pseudo-allergic reactions. Scientific reports 17 32999394
2008 The effect of deletion of the orphan G - protein coupled receptor (GPCR) gene MrgE on pain-like behaviours in mice. Molecular pain 14 18197975
2023 Identifying G protein-coupled receptors involved in adipose tissue function using the innovative RNA-seq database FATTLAS. iScience 6 37766984
2021 Exploration of potential therapeutic targets for stroke based on the GEO database. Annals of translational medicine 5 35071453
2025 USP45 Represses Melanoma Development by Deubiquitinating and Stabilizing Tumor Suppressor MRGPRF. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40788071
2025 Gut microbes-spinal connection is required for itch sensation. Gut microbes 2 40289281
2025 Investigating the effects of global gene knockout of MrgF on motor performance and pain sensitivity in mice. Hereditas 0 40033362
2024 GPR168 functions as a tumor suppressor in mouse melanoma by restraining Akt signaling pathway. PloS one 0 38805406
2023 The orphan MRGPRF receptor is expressed in entero-endocrine cells of the human gut mucosa. Cell and tissue research 0 37314493

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