Affinage

GPRC5A

Retinoic acid-induced protein 3 · UniProt Q8NFJ5

Length
357 aa
Mass
40.3 kDa
Annotated
2026-06-10
89 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPRC5A is a retinoic-acid-inducible orphan GPCR of epithelial tissues that functions context-dependently as a lung tumor suppressor and, in other settings, as an oncogenic signaling node (PMID:18000218, PMID:30143543). Its transcription is directly driven by retinoic acid through a functional DR5 response element at -64 bp bound by RAR/RXR heterodimers (PMID:19279407, PMID:14706456), and is repressed by NF-κB: phospho-S276 RelA/p65 forms a complex with RARα/β at the same response element, suppresses H3K9 acetylation, and displaces RNA Pol II (PMID:36413416). In normal lung epithelium GPRC5A restrains multiple oncogenic pathways: it physically interacts with EGFR via its transmembrane domain to inhibit EGFR–STAT3 signaling (PMID:25744720), localizes to the ER membrane where it binds the eIF4F complex through its extracellular loops to suppress cap-dependent translation of secreted and membrane proteins including EGFR itself (PMID:27273304), stabilizes the STAT3 inhibitor Socs3 (PMID:20959490), and limits NF-κB-driven inflammation (PMID:20354164, PMID:25714996). EGFR reciprocally inactivates GPRC5A by phosphorylating C-terminal double-tyrosine motifs (Y317/Y320, Y347/Y350), abolishing its tumor-suppressive activity, and this phosphorylated form predominates in NSCLC (PMID:25311788). Loss of GPRC5A drives tumorigenesis through EGFR-dependent MDM2 stabilization and p53 suppression (PMID:29992578) and PGE2-mediated immunosuppression (PMID:32060421). In other tissue and tumor contexts GPRC5A acts oncogenically by activating YAP1 signaling through HIF, cAMP–CREB, or WWP1-mediated LATS1 degradation (PMID:30143543, PMID:36735162, PMID:39550386), by recruiting mTORC1 to lysosomes through LAMTOR1 stabilization (PMID:38335844), and by interacting with integrin β1/EphA2 (PMID:27715394), ABCB1 (PMID:38426412), and GLUT1 (PMID:40744179). Microbiota-derived aromatic monoamines act as GPRC5A agonists that stimulate β-arrestin recruitment, with 7-fluorotryptamine a more potent synthetic agonist (PMID:37248411).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 High

    Established the transcriptional control of GPRC5A by mapping its promoter architecture and identifying retinoic acid responsiveness, the founding feature of this gene.

    Evidence Promoter truncation, EMSA, and site-directed mutation analysis identifying GC boxes, Sp1/AP1/AP2 sites, and a DR5 retinoic acid response element

    PMID:14706456

    Open questions at the time
    • Did not establish which RAR/RXR isoforms bind in vivo
    • No functional consequence of induction defined
  2. 2005 Medium

    Asked how GPRC5A intersects with tumor-suppressor circuits and showed p53 directly represses its promoter, with context-dependent growth effects.

    Evidence ChIP of p53 at RAI3 promoter, expression profiling across p53-status lines, siRNA knockdown, and anchorage-independent growth assay

    PMID:15659406

    Open questions at the time
    • Pro-growth role conflicts with later tumor-suppressor data
    • Mechanism of p53-mediated repression not resolved
  3. 2007 High

    Resolved the central question of GPRC5A's physiological role by demonstrating it is a lung tumor suppressor in vivo.

    Evidence Gprc5a homologous-recombination knockout mice with spontaneous lung tumors plus colony formation rescue across multiple cell lines

    PMID:18000218

    Open questions at the time
    • Molecular mechanism of suppression not yet defined
    • Did not address signaling pathways downstream
  4. 2009 High

    Defined the precise cis-element and trans-factors mediating retinoic acid induction, anchoring GPRC5A in retinoid signaling.

    Evidence EMSA with competitor oligos and ChIP showing RAR-α/γ and RXR-α/β binding the functional DR5III element

    PMID:19279407

    Open questions at the time
    • Did not connect transcriptional induction to downstream function
  5. 2010 High

    Identified the downstream signaling pathways deranged by GPRC5A loss, linking it to STAT3 and NF-κB-driven inflammation.

    Evidence KO + rescue Western blots for STAT3-pY705/Socs3, dominant-negative STAT3, JAK2 inhibition, NF-κB reporter, cytokine, and macrophage migration assays

    PMID:20354164 PMID:20959490

    Open questions at the time
    • Whether STAT3 and NF-κB effects are direct or downstream of EGFR not yet resolved
    • Mechanism of Socs3 stabilization unknown
  6. 2014 High

    Explained how GPRC5A is functionally silenced in cancer by identifying EGFR-mediated tyrosine phosphorylation as an inactivating switch.

    Evidence IP-Western, site-directed Y-to-F mutagenesis, EGF stimulation, anchorage-independent growth, and phospho-specific IHC on human NSCLC

    PMID:25311788

    Open questions at the time
    • Structural basis of phosphorylation-induced inactivation unknown
    • Direct vs. indirect EGFR kinase action on GPRC5A not fully resolved
  7. 2015 High

    Established the direct physical mechanism of EGFR inhibition by GPRC5A through its transmembrane domain.

    Evidence Co-IP, domain-deletion mutagenesis, and EGFR/STAT3 signaling assays in Gprc5a-/- MTEC versus wild-type

    PMID:25744720

    Open questions at the time
    • No structural model of the GPRC5A–EGFR transmembrane interface
    • Stoichiometry and dynamics of complex unknown
  8. 2016 High

    Uncovered a non-canonical, receptor-independent function: GPRC5A suppresses cap-dependent translation at the ER by binding eIF4F.

    Evidence ER fractionation, Co-IP with eIF4F components, extracellular-loop deletion mapping, EGFR translation-rate measurement, and in vivo irradiation tumor model

    PMID:27273304

    Open questions at the time
    • Breadth of translationally repressed targets not defined
    • How an ER membrane GPCR engages cap machinery structurally unclear
  9. 2018 Medium

    Expanded the tumor-suppressor mechanism to p53 pathway control via EGFR-dependent MDM2 stabilization, and identified new adhesion and hypoxia roles.

    Evidence KO-derived cells with Nutlin-3a/Erlotinib epistasis; CRISPR KO with ITGB1/FAK/RhoA-Rac1 readouts and EphA2 Co-IP; SILAC proteomics with HIF-GPRC5A-YAP epistasis

    PMID:27715394 PMID:29992578 PMID:30143543

    Open questions at the time
    • YAP activation by GPRC5A appears oncogenic, opposite to lung tumor-suppressor role
    • EphA2 interaction rests on single Co-IP
    • Tissue determinants of opposing roles undefined
  10. 2020 High

    Resolved the long-standing orphan status by identifying microbiota-derived aromatic monoamines as bona fide GPRC5A agonists.

    Evidence Photoaffinity chemoproteomics, β-arrestin recruitment assay, metabolomics, and synthetic SAR (7-fluorotryptamine)

    PMID:37248411

    Open questions at the time
    • G-protein coupling and downstream signaling of liganded receptor not defined
    • Physiological relevance of microbiota ligands in vivo unclear
  11. 2020 Medium

    Connected GPRC5A loss to immunosuppressive metastasis and to inflammatory lung injury, broadening its epithelial-protective role.

    Evidence Ptges double-KO with immune-competent vs nude host epistasis and MDSC/T-cell flow cytometry; LPS-ALI model with epithelium-specific IκBα super-repressor rescue

    PMID:25714996 PMID:32060421

    Open questions at the time
    • Whether PGE2 axis is direct GPRC5A output or downstream NF-κB unclear
    • Cell-type specificity of NF-κB regulation incompletely mapped
  12. 2023 High

    Defined the epigenetic mechanism by which NF-κB silences GPRC5A, closing the regulatory loop between inflammation and receptor loss.

    Evidence ChIP for p65/RAR/Pol II/H3K9ac, p65–RARα/β Co-IP, p65-S276 phospho-mutant epistasis, and HDAC vs DNMT inhibitor rescue

    PMID:36413416

    Open questions at the time
    • HDAC isoform mediating H3K9 deacetylation not identified
    • Generality across non-lung epithelia untested
  13. 2024 Medium

    Detailed the oncogenic effector mechanisms of GPRC5A across tumor types: mTORC1 activation, YAP1 induction, and drug-efflux/transporter regulation.

    Evidence MS/Co-IP with LAMTOR1 and m6A MeRIP in TNBC; STAT3-TNS4 ChIP in gallbladder cancer; WWP1–LATS1 ubiquitination with YAP inhibitor rescue in ESCC; ABCB1 Co-IP with KO drug-sensitivity

    PMID:38335844 PMID:38426412 PMID:38942137 PMID:39550386

    Open questions at the time
    • Each interaction rests largely on single-lab Co-IP
    • How a single receptor switches between tumor-suppressor and oncogenic outputs unresolved
  14. 2025 Low

    Identified new plasma-membrane regulatory inputs and outputs: Galectin-3-driven internalization, GLUT1 metabolic coupling, and cathepsin-G cleavage releasing a nuclear C-terminal fragment.

    Evidence Gal-3 interactomics/internalization assay in CRC; GLUT1 Co-IP/stability/glucose-uptake rescue in glioblastoma; N-TAILS cleavage mapping with peptide rescue in keratinocytes

    PMID:39812615 PMID:40744179 PMID:41090797

    Open questions at the time
    • GLUT1 and cathepsin-G findings are single low-confidence studies awaiting independent confirmation
    • Functional significance of nuclear C-terminal fragment undefined
    • Whether Gal-3 internalization regulates signaling output untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what determines whether GPRC5A acts as a tumor suppressor or oncogene in a given tissue, and how ligand engagement, G-protein coupling, and the diverse interactome are mechanistically integrated.
  • No unifying model reconciling tumor-suppressor and oncogenic functions
  • Downstream G-protein signaling of liganded receptor uncharacterized
  • No high-resolution structure of GPRC5A or its complexes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0045182 translation regulator activity 1 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
ABCB1BMPR1AEGFREIF4FEPHA2GLUT1LAMTOR1WWP1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Gprc5a functions as a lung tumor suppressor: Gprc5a knockout mice developed lung adenomas (76%) and adenocarcinomas (17%) compared to ~10% adenomas in wild-type mice; ectopic GPRC5A expression in human embryonic kidney, NSCLC, and mouse lung adenocarcinoma cells suppressed colony formation in semisolid medium by 68–91%. Homologous recombination knockout mouse model; colony formation assay with GPRC5A transfection Journal of the National Cancer Institute High 18000218
2010 Gprc5a loss in mouse lung epithelial cells causes persistent STAT3 tyrosine-705 phosphorylation driven by autocrine leukemia inhibitory factor (LIF) secretion. Gprc5a(-/-) cells showed reduced levels of the endogenous STAT3 inhibitor Socs3 compared to wild-type cells; re-expression of Gprc5a in knockout cells stabilized Socs3. Inhibition of JAK2 or dominant-negative STAT3(Y705F) increased apoptosis and reduced colony formation in knockout cells. Western blot (STAT3 phosphorylation, Socs3), dominant-negative STAT3 transfection, JAK2 inhibitor (AG490), colony formation assay, re-expression of Gprc5a in knockout cells Cancer research High 20959490
2010 Gprc5a loss in lung airway epithelial cells enhances constitutive and stimulus-induced NF-κB activation, leading to increased pro-inflammatory cytokine/chemokine production that promotes macrophage infiltration and a tumor-promoting microenvironment. Re-expression of Gprc5a in knockout adenocarcinoma cells partially reversed the elevated NF-κB activation. NF-κB reporter assays, cytokine measurement, p65 siRNA knockdown and Gprc5a siRNA knockdown in paired wild-type and knockout tracheal epithelial cells, macrophage migration assay Cancer prevention research (Philadelphia, Pa.) High 20354164
2015 GPRC5A physically interacts with EGFR through its transmembrane domain and negatively modulates EGFR and downstream STAT3 signaling. The transmembrane domain was required for EGFR inhibitory activity as shown by domain-deletion analysis. Mouse tracheal epithelial cells from Gprc5a(-/-) mice showed elevated EGFR/STAT3 signaling reversed by GPRC5A re-expression. Co-immunoprecipitation, domain-deletion mutagenesis, EGFR/STAT3 signaling assays in Gprc5a(-/-) MTEC vs. wild-type, ectopic GPRC5A expression in NSCLC cells Cancer research High 25744720
2014 EGFR phosphorylates GPRC5A at two conserved double-tyrosine motifs (Y317/Y320 and Y347/Y350) in the C-terminal tail. EGF-induced phosphorylation disrupts GPRC5A-mediated suppression of anchorage-independent growth. The phosphorylation-resistant mutant GPRC5A-4F maintained tumor suppressive activity. GPRC5A was non-phosphorylated in normal lung tissue but highly tyrosine-phosphorylated in NSCLC tissues. IP-Western blot, site-directed mutagenesis (Y317/320/347/350F), EGF stimulation assays, anchorage-independent growth assay, IHC with phospho-specific antibodies on human tumor tissue Molecular cancer High 25311788
2016 GPRC5A localizes to the endoplasmic reticulum membrane and suppresses protein synthesis of secreted/membrane-bound proteins (including EGFR) by directly binding the eIF4F translation initiation complex through its two middle extracellular loops, thereby disturbing assembly of the eIF4F complex on the mRNA cap. Subcellular fractionation/ER localization, co-immunoprecipitation of GPRC5A with eIF4F components, domain-deletion analysis (extracellular loops), measurement of EGFR translation rate, in vivo ionizing radiation lung tumorigenesis model in Gprc5a(-/-) mice Nature communications High 27273304
2009 Retinoic acid induces GPRC5A transcription through a functional retinoic acid response element DR5III (5'-TGT CCC TCT GCT CAC CC-3') at -64 bp upstream of the transcription start site. RAR-alpha/gamma and RXR-alpha/beta bind this element in intact cells. DR5I and DR5II are non-functional for GPRC5A induction. Electrophoretic mobility shift assay (EMSA) with wild-type and mutated oligonucleotides; chromatin immunoprecipitation (ChIP); promoter truncation/deletion analysis Cancer biology & therapy High 19279407
2004 The Rai3/Gprc5a promoter contains functional GC boxes and Sp1-, AP1-, AP2-binding sites, and a functional retinoic acid response element (direct repeat with 5-bp spacer at -64 bp) that mediates retinoic acid induction, identified by promoter truncation, EMSA, and mutation analysis. Promoter truncation analysis, EMSA, site-directed mutation analysis Genomics High 14706456
2018 GPRC5A modulates integrin β1 (ITGB1)-mediated cell adhesion to extracellular matrix substrates. CRISPR/Cas9 knockout of GPRC5A reduced ITGB1 protein expression, impaired FAK phosphorylation, and lowered RhoA and Rac1 GTPase activity. GPRC5A also directly interacts with the receptor tyrosine kinase EphA2. CRISPR/Cas9 knockout, RNAi knockdown, cell adhesion assays to ECM substrates, Western blot (ITGB1, pFAK), small GTPase activity assays, co-immunoprecipitation (GPRC5A–EphA2) Cell adhesion & migration Medium 27715394
2018 GPRC5A deficiency leads to dysregulated MDM2 stabilization via activated EGFR signaling (independent of transcription), resulting in p53 pathway suppression and promotion of lung tumor development. Targeting MDM2 with Nutlin-3a or shRNA in Gprc5a-ko-derived cells restored p53 signaling and reduced tumorigenicity. Gprc5a knockout mouse-derived tumor cell lines, MDM2 inhibitor (Nutlin-3a) and shRNA, EGFR inhibitor (Erlotinib) and shRNA, Western blot, colony formation, IHC of human lung cancer tissues International journal of cancer Medium 29992578
2018 In cancer cell adaptation to hypoxia, HIFs directly activate GPRC5A transcription, and GPRC5A in turn activates the Hippo pathway effector YAP and its anti-apoptotic target BCL2L1. The apoptosis induced by GPRC5A depletion under hypoxia was rescued by constitutively active YAP, placing GPRC5A between HIF and YAP in a survival axis. SILAC-based proteomics (hypoxia induction), genetic knockdown/knockout in vitro and in vivo, HIF ChIP-seq/reporter analysis, constitutively active YAP rescue, YAP target gene measurement EMBO molecular medicine High 30143543
2020 PTGES/PGE2 signaling in Gprc5a-ko mouse lung tumors promotes metastasis primarily through immunosuppression: tumor cell-intrinsic PGE2 confers resistance to T-cell cytotoxicity and induces cytokines for MDSC recruitment, suppressing T-cell immunity. PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Ptges knockout in tumor cells, immune-competent vs. nude mouse transplantation epistasis, cytokine measurement, MDSC/T-cell flow cytometry, PTGES inhibitor treatment in Gprc5a-ko mice Oncogene Medium 32060421
2015 Gprc5a deficiency in mice confers susceptibility to LPS-induced acute lung injury through enhanced NF-κB signaling specifically in bronchioalveolar epithelium. Expression of a super-repressor IκBα specifically in Gprc5a-ko bronchioalveolar epithelium alleviated LPS-induced pulmonary injury and inflammatory response. LPS-induced ALI model in Gprc5a-ko and wild-type mice, cytokine/chemokine measurement, pulmonary edema assessment, epithelium-specific IκBα super-repressor transgene rescue Cell cycle (Georgetown, Tex.) Medium 25714996
2023 NF-κB (specifically RelA/p65, phosphorylated on serine 276) represses GPRC5A transcription by forming a complex with retinoic acid receptor α/β (RARα/β) and being recruited to the RA response element at the GPRC5A promoter, disrupting RNA Pol II binding. This epigenetic repression involves suppression of acetylated histone H3K9 (H3K9ac) but not DNA methylation of CpG islands. HDAC inhibitor but not DNA methylation inhibitor restored GPRC5A expression. ChIP assay (p65, RAR, RNA Pol II, H3K9ac), Co-IP (p65–RARα/β), site-directed mutagenesis (p65 S276), HDAC inhibitor and DNA methylation inhibitor treatment, in vivo NF-κB activation model JCI insight High 36413416
2005 p53 interacts with the RAI3/GPRC5A promoter and represses its expression at the onset of apoptosis. RAI3 mRNA is elevated in tumor cell lines expressing mutant p53 and relatively repressed in lines with wild-type p53. Ectopic RAI3 expression in 293 cells promotes anchorage-independent growth, and siRNA depletion of RAI3 in AsPc-1 pancreatic cells induces morphological change. Chromatin immunoprecipitation (ChIP) of p53 at RAI3 promoter, gene expression profiling, siRNA knockdown, anchorage-independent growth assay The Journal of biological chemistry Medium 15659406
2020 Chemoproteomics identified aromatic monoamines (microbiota-derived indole metabolites) as ligands that bind the orphan receptor GPRC5A and stimulate β-arrestin recruitment. 7-fluorotryptamine was identified as a more potent synthetic agonist. Specific amino acid decarboxylase-expressing microbiota species produce these agonists. Photoaffinity chemical reporters/chemoproteomics, β-arrestin recruitment assay, metabolomic profiling, synthetic monoamine derivative screening Nature chemical biology High 37248411
2020 Chemotherapy (cisplatin/carboplatin) in ovarian cancer triggers an ERK1/2–RSK1/2–EphA2(S897)–GPRC5A signaling axis associated with chemoresistance. Pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2–GPRC5A co-regulation, shifting signaling to canonical tumor-suppressive EphA2 tyrosine phosphorylation and EphA2 downregulation. RSK1/2 pharmacological inhibition and knockdown, EphA2-S897 phosphorylation assays, Co-immunoprecipitation (EphA2–GPRC5A), patient tumor samples, apoptosis assays EMBO molecular medicine Medium 32115889
2014 miR-103a-3p targets two sites in the 5' UTR of GPRC5A mRNA (not the 3' UTR) in a seed-dependent manner, reducing GPRC5A mRNA and protein levels in normal epithelial and pancreatic cancer cell lines. Ectopic sponges containing the wild-type 5' UTR targets reduced miR-103a-3p levels and increased GPRC5A mRNA and protein. miRNA target site validation (luciferase or expression reporter with mutated 5' UTR sites), sponge experiments, qRT-PCR and Western blot in multiple cell lines RNA (New York, N.Y.) Medium 24984703
2016 HuR (RNA-binding protein) binds GPRC5A mRNA at an AU-rich binding site and stabilizes it following gemcitabine treatment, causing a monotonic increase in GPRC5A protein levels. GPRC5A knockdown sensitized pancreatic cancer cells to gemcitabine. RNA immunoprecipitation/RIP identifying HuR–GPRC5A mRNA interaction, Western blot time-course after gemcitabine, GPRC5A knockdown + gemcitabine combination assay Cell death & disease Medium 27415424
2018 GPRC5A knockout in pancreatic cancer cells increased phosphorylation of GSK-3β (Ser9), reduced cell proliferation and migration, and suppressed resistance to gemcitabine, oxaliplatin, and fluorouracil. CRISPR/Cas9 knockout in MIA PaCa-2 and TB32047 cells, proliferation and migration assays, drug resistance assays, Western blot for pGSK-3β International journal of molecular sciences Medium 29949874
2024 GPRC5A interacts with LAMTOR1, inhibiting its ubiquitination-dependent degradation, thereby recruiting mTORC1 to lysosomes and activating the mTORC1/p70S6K signaling pathway. GPRC5A mRNA is post-transcriptionally regulated by m6A methylation via the METTL3/YTHDF1 axis. Mass spectrometry, Co-IP, immunofluorescence colocalization (GPRC5A–LAMTOR1), MeRIP (m6A sequencing), dual-luciferase reporter, knockdown/overexpression in TNBC cells and in vivo models Drug resistance updates Medium 38335844
2024 GPRC5A promotes gallbladder cancer metastasis by activating JAK2-STAT3 signaling, which induces expression of TNS4 by STAT3 binding to the TNS4 promoter. ChIP confirmed STAT3 binding at the TNS4 promoter. GPRC5A knockdown in GBC cells (in vitro and in vivo), RNA-seq, Western blot, ChIP (STAT3 at TNS4 promoter), immunohistochemistry Cancer letters Medium 38942137
2024 GPRC5A directly binds ABCB1 (P-glycoprotein) and reduces its expression. Gprc5a-deficient mouse tracheal epithelial cells and lung tissues showed higher ABCB1 expression, and Gprc5a-ko cells were more sensitive to tariquidar (ABCB1 inhibitor) and doxorubicin. ABCB1 knockout in Gprc5a-/- tumor cells reduced tumor growth in vivo. Immunofluorescence colocalization, co-immunoprecipitation (GPRC5A–ABCB1), Western blot, RT-PCR, Gprc5a-ko mouse tissues, cell sensitivity assays, xenograft tumor model Chinese medical sciences journal Medium 38426412
2023 GPRC5A promotes pancreatic cancer cell proliferation and migration by positively regulating YAP1 transcription through the cAMP–CREB signaling axis. The pro-proliferative and migratory effects of GPRC5A were rescued by YAP1 inhibition. GPRC5A knockdown/overexpression in pancreatic cancer cells, cAMP measurement, CREB reporter assay, YAP1 rescue experiment, cytosolic/nuclear distribution assay, xenograft model Discover oncology Medium 36735162
2024 GPRC5A potentially interacts with WWP1 E3 ubiquitin ligase, facilitating polyubiquitination and degradation of LATS1, thereby activating YAP1 signaling and promoting lung metastasis in esophageal squamous cell carcinoma. Targeting YAP1 with CA3 or TED-347 diminished early implantation and macro-metastases. Single-cell RNA sequencing, Co-immunoprecipitation (GPRC5A–WWP1), ubiquitination assay (LATS1), YAP1 inhibitor rescue, in vivo metastasis model, patient cohort (n=148) Nature communications Medium 39550386
2017 GPRC5A overexpression suppressed IL-6-induced STAT3 activation and inhibited anchorage-independent growth in head and neck squamous cell carcinoma cells, placing GPRC5A as a negative regulator of STAT3 in this context. Stable GPRC5A transfection in HNSCC cells, IL-6 stimulation, Western blot (pSTAT3), anchorage-independent growth assay, IHC of clinical HNSCC samples Cancer cell international Medium 28270740
2017 RAI3/GPRC5A knockdown in human adipose-derived stem cells promoted adipogenic differentiation by decreasing β-catenin levels. Activation of the β-catenin pathway by lithium chloride abolished the effect of RAI3 knockdown on adipogenesis. siRNA knockdown of RAI3 in hASCs, adipogenic differentiation assays (in vitro and in vivo xenograft), Western blot (β-catenin), lithium chloride (Wnt/β-catenin activator) rescue experiment Biochemical and biophysical research communications Low 28870805
2020 RAI3/GPRC5A knockdown in bone marrow mesenchymal stem cells promoted osteogenic differentiation by upregulating phosphorylated STAT3. The JAK2 inhibitor AG-490 reversed the enhancing effect of RAI3 knockdown on osteogenesis. siRNA knockdown, osteogenic differentiation assays (in vitro and in vivo), Western blot (pSTAT3), pharmacological JAK2 inhibitor AG-490 rescue Biochemical and biophysical research communications Low 32014253
2024 Gprc5a is a PTH-inducible gene: PTH treatment induces Gprc5a expression in osteoblast-like cells and mouse femurs via the cAMP pathway (cAMP response element in promoter), independent of new protein synthesis. Gprc5a negatively regulates osteoblast proliferation and differentiation by interacting with BMPR1A and suppressing BMP-2 signaling. PTH stimulation in MC3T3-E1, ROS17/2.8, and mouse femurs; cycloheximide (protein synthesis inhibition); cAMP pathway inhibitors; reporter analysis of GPRC5A promoter; Gprc5a knockdown (MTT, BrdU, mineralization assay); Co-immunoprecipitation (Gprc5a–BMPR1A); constitutively active BMP receptor constructs Journal of cellular physiology Medium 38769895
2021 GPRC5A acts as a negative regulator of the PI3K/Akt signaling pathway in triple-negative breast cancer cells. GPRC5A overexpression promoted apoptosis via the intrinsic pathway, activating caspase-3 and caspase-9, and this was inhibited by a PI3K/Akt activator. GPRC5A knockdown inhibited apoptosis, which was partially restored by a PI3K/Akt inhibitor. GPRC5A overexpression/knockdown in TNBC cells, RNA-seq pathway analysis, PI3K/Akt activator/inhibitor rescue experiments, caspase activation assays, in vivo tumor growth Frontiers in oncology Medium 33680947
2018 GPRC5A modulates TGF-β signaling and EGFR activation in cultured podocytes. Gprc5a-deficient mice developed thickening of the glomerular basement membrane, mesangial cell activation, increased albuminuria, and more severe diabetic nephropathy histology after streptozotocin-induced diabetes. Gprc5a knockout mouse model, streptozotocin-induced diabetes, glomerular histology/EM, albumin measurement, TGF-β and EGFR signaling assays in cultured podocytes Journal of the American Society of Nephrology : JASN Medium 29636387
2020 TPA (phorbol ester) strongly induces GPRC5A mRNA and protein expression at the plasma membrane via a PKC/Ca²⁺→MEK1/2 signaling axis. PKC inhibitor Gö6983, Ca²⁺ chelator BAPTA-AM, and MEK1/2 inhibitor U0126 each suppressed TPA-induced GPRC5A upregulation. PKA inhibitor H-89 also partially reduced induction. TPA stimulation of T84 cells, pharmacological inhibitors (Gö6983, BAPTA-AM, U0126, H-89, GSK650394), RT-PCR, Western blot, confocal microscopy Archives of biochemistry and biophysics Medium 32339486
2025 Galectin-3 (Gal-3) directly binds glycosylated GPRC5A at the plasma membrane and stimulates GPRC5A internalization/endocytosis in colorectal cancer cells. This interaction is independent of ATRA-induced GPRC5A upregulation. Proteomic analysis of endogenous Gal-3 immunoprecipitates (interactomic assay), Co-IP, extracellular recombinant Gal-3 stimulation, GPRC5A internalization assay, immunofluorescence in SW480 cells Cells Medium 41090797
2025 GPRC5A interacts with the glycolytic transporter GLUT1, influencing glucose uptake and glycolysis in glioblastoma. Silencing GPRC5A reduced GLUT1 stability and glucose uptake, increasing TMZ sensitivity, and this effect was reversible by GLUT1 overexpression. Co-immunoprecipitation (GPRC5A–GLUT1), GLUT1 stability assay, glucose uptake measurement, GPRC5A knockdown ± GLUT1 overexpression rescue, TMZ sensitivity assay, in vivo xenograft International journal of biological macromolecules Low 40744179
2025 In keratinocytes, GPRC5A undergoes proteolytic cleavage by cathepsin G, releasing its C-terminal region which translocates to the nucleus. GPRC5A knockdown enhanced cell adhesion while reducing cell migration and differentiation; these effects were reversed by addition of a recombinant polypeptide mimicking the C-terminal region. GPRC5A expression is re-induced during wound healing at leading edges. N-TAILS protease cleavage site analysis, cathepsin G identification, shRNA knockdown in N/TERT-1 keratinocytes, cell adhesion/migration/differentiation assays, C-terminal peptide rescue, ex vivo burn wound model FASEB journal Low 39812615

Source papers

Stage 0 corpus · 89 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2024 Methylation of GPRC5A promotes liver metastasis and docetaxel resistance through activating mTOR signaling pathway in triple negative breast cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 144 38335844
2016 Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells. European urology 119 27387124
2014 MiR-103a-3p targets the 5' UTR of GPRC5A in pancreatic cells. RNA (New York, N.Y.) 114 24984703
2007 Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene. Journal of the National Cancer Institute 103 18000218
2018 circGprc5a Promoted Bladder Oncogenesis and Metastasis through Gprc5a-Targeting Peptide. Molecular therapy. Nucleic acids 78 30497053
2018 Cancer cell adaptation to hypoxia involves a HIF-GPRC5A-YAP axis. EMBO molecular medicine 75 30143543
2010 Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis. Cancer prevention research (Philadelphia, Pa.) 69 20354164
2019 Elevated levels of hsa_circ_006100 in gastric cancer promote cell growth and metastasis via miR-195/GPRC5A signalling. Cell proliferation 68 31318114
2015 Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling. Cancer research 67 25744720
2020 PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model. Oncogene 66 32060421
2014 The emerging roles of GPRC5A in diseases. Oncoscience 56 25621293
2010 Gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent Stat3 signaling induced by autocrine leukemia inhibitory factor. Cancer research 53 20959490
2020 Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer. EMBO molecular medicine 49 32115889
2012 G-protein coupled receptor family C, group 5, member A (GPRC5A) expression is decreased in the adjacent field and normal bronchial epithelia of patients with chronic obstructive pulmonary disease and non-small-cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 48 23154545
2017 Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN-1 induced oxidative stress. International journal of cancer 43 28316092
2017 Integrated MicroRNA-mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in Gastric Cancer by Targeting CKS1B, CXCL1 and GPRC5A. International journal of molecular sciences 42 29283424
2016 GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR. Cell death & disease 42 27415424
2019 GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer. International journal of cancer 41 31276604
2005 Identification of RAI3 as a therapeutic target for breast cancer. Endocrine-related cancer 41 15788639
2005 Integrative genomics revealed RAI3 is a cell growth-promoting gene and a novel P53 transcriptional target. The Journal of biological chemistry 39 15659406
2021 BMSC-derived exosomes ameliorate sulfur mustard-induced acute lung injury by regulating the GPRC5A-YAP axis. Acta pharmacologica Sinica 37 33654219
2018 The Effect of GPRC5a on the Proliferation, Migration Ability, Chemotherapy Resistance, and Phosphorylation of GSK-3β in Pancreatic Cancer. International journal of molecular sciences 37 29949874
2018 GPRC5A: An Emerging Biomarker in Human Cancer. BioMed research international 36 30417009
2010 Comparative functional genomics analysis of NNK tobacco-carcinogen induced lung adenocarcinoma development in Gprc5a-knockout mice. PloS one 34 20686609
2010 A Gprc5a tumor suppressor loss of expression signature is conserved, prevalent, and associated with survival in human lung adenocarcinomas. Neoplasia (New York, N.Y.) 32 20563252
2023 Chemoproteomics reveals microbiota-derived aromatic monoamine agonists for GPRC5A. Nature chemical biology 31 37248411
2017 Repression of GPRC5A is associated with activated STAT3, which contributes to tumor progression of head and neck squamous cell carcinoma. Cancer cell international 31 28270740
2016 GPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis. Nature communications 30 27273304
2005 Normal lung development in RAIG1-deficient mice despite unique lung epithelium-specific expression. American journal of respiratory cell and molecular biology 30 15677768
2014 High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients. International journal of cancer 29 24470238
2012 Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation. Molecular cancer 29 22239913
2023 Exosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling. Nature communications 28 37673874
2018 GPRC5A deficiency leads to dysregulated MDM2 via activated EGFR signaling for lung tumor development. International journal of cancer 27 29992578
2014 EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer. Molecular cancer 27 25311788
2015 Gprc5a-deficiency confers susceptibility to endotoxin-induced acute lung injury via NF-κB pathway. Cell cycle (Georgetown, Tex.) 25 25714996
2009 Production and characterisation of monoclonal antibodies against RAI3 and its expression in human breast cancer. BMC cancer 25 19552806
2017 Development of Kras mutant lung adenocarcinoma in mice with knockout of the airway lineage-specific gene Gprc5a. International journal of cancer 23 28653505
2009 Mechanisms underlying the induction of the putative human tumor suppressor GPRC5A by retinoic acid. Cancer biology & therapy 22 19279407
2022 MiR-135b-5p is an oncogene in pancreatic cancer to regulate GPRC5A expression by targeting transcription factor KLF4. Cell death discovery 21 35027543
2018 Depletion of Gprc5a Promotes Development of Diabetic Nephropathy. Journal of the American Society of Nephrology : JASN 21 29636387
2016 GPRC5A exerts its tumor-suppressive effects in breast cancer cells by inhibiting EGFR and its downstream pathway. Oncology reports 21 27599526
2020 Integrated Single-Cell RNA-Sequencing Analysis of Aquaporin 5-Expressing Mouse Lung Epithelial Cells Identifies GPRC5A as a Novel Validated Type I Cell Surface Marker. Cells 20 33187367
2021 DSCAM-AS1 accelerates cell proliferation and migration in osteosarcoma through miR-186-5p/GPRC5A signaling. Cancer biomarkers : section A of Disease markers 17 32865178
2019 microRNA-367-3p regulation of GPRC5A is suppressed in ischemic stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 17 31296130
2004 Characterization of the murine orphan G-protein-coupled receptor gene Rai3 and its regulation by retinoic acid. Genomics 17 14706456
2021 Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis. Open medicine (Warsaw, Poland) 15 34553078
2017 Orphan G protein-coupled receptor GPRC5A modulates integrin β1-mediated epithelial cell adhesion. Cell adhesion & migration 15 27715394
2017 Gprc5a-knockout mouse lung epithelial cells predicts ceruloplasmin, lipocalin 2 and periostin as potential biomarkers at early stages of lung tumorigenesis. Oncotarget 15 28088789
2020 Circular RNA Gprc5a Promotes HCC Progression by Activating YAP1/TEAD1 Signalling Pathway by Sponging miR-1283. OncoTargets and therapy 14 32547082
2022 DNA methyltransferase 1 inhibits microRNA-497 and elevates GPRC5A expression to promote chemotherapy resistance and metastasis in breast cancer. Cancer cell international 13 35255904
2019 Gprc5a depletion enhances the risk of smoking-induced lung tumorigenesis and mortality. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 13 30901718
2019 Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations. Frontiers in oncology 13 31001473
2017 Lung cancer suppressor gene GPRC5A mediates p53 activity in non‑small cell lung cancer cells in vitro. Molecular medicine reports 13 28849235
2023 The G protein-coupled receptor GPRC5A-a phorbol ester and retinoic acid-induced orphan receptor with roles in cancer, inflammation, and immunity. Biochemistry and cell biology = Biochimie et biologie cellulaire 12 37467514
2024 GPRC5A promotes gallbladder cancer metastasis by upregulating TNS4 via the JAK2-STAT3 pathway. Cancer letters 11 38942137
2023 Upregulated GPRC5A disrupting the Hippo pathway promotes the proliferation and migration of pancreatic cancer cells via the cAMP-CREB axis. Discover oncology 11 36735162
2021 GPRC5A Is a Negative Regulator of the Pro-Survival PI3K/Akt Signaling Pathway in Triple-Negative Breast Cancer. Frontiers in oncology 11 33680947
2020 Downregulation of MiR-218 can alleviate high-glucose-induced renal proximal tubule injury by targeting GPRC5A. Bioscience, biotechnology, and biochemistry 11 32028854
2015 Epithelial neoplasia coincides with exacerbated injury and fibrotic response in the lungs of Gprc5a-knockout mice following silica exposure. Oncotarget 11 26447616
2024 GPRC5A promotes lung colonization of esophageal squamous cell carcinoma. Nature communications 10 39550386
2023 NF-κB represses retinoic acid receptor-mediated GPRC5A transactivation in lung epithelial cells to promote neoplasia. JCI insight 10 36413416
2021 IMUP and GPRC5A: two newly identified risk score indicators in pancreatic ductal adenocarcinoma. Cancer cell international 9 34819098
2019 miR‑342 inhibits glioma cell proliferation by targeting GPRC5A. Molecular medicine reports 9 31115523
2018 Clinical significance of reduced GPRC5A expression in surgically resected non-small cell lung cancer. Oncology letters 9 30655793
2020 Identification of Sca-1+Abcg1+ bronchioalveolar epithelial cells as the origin of lung adenocarcinoma in Gprc5a-knockout mouse model through the interaction between lung progenitor AT2 and Lgr5 cells. Oncogene 8 32157214
2020 RhoA/C inhibits proliferation by inducing the synthesis of GPRC5A. Scientific reports 8 32719397
2020 Circ_0000144 functions as a miR-623 sponge to enhance gastric cancer progression via up-regulating GPRC5A. Bioscience reports 7 32766708
2025 GPRC5A/CXCL8/NLRP3-mediated neutrophil extracellular traps drive gemcitabine-nab-paclitaxel resistance in pancreatic adenocarcinoma. Cancer biology & medicine 5 40665634
2024 Gprc5a is a novel parathyroid hormone-inducible gene and negatively regulates osteoblast proliferation and differentiation. Journal of cellular physiology 5 38769895
2020 RAI3 knockdown enhances osteogenic differentiation of bone marrow mesenchymal stem cells via STAT3 signaling pathway. Biochemical and biophysical research communications 4 32014253
2020 GPRC5a suppresses the proliferation of non-small cell lung cancer under wild type p53 background. Experimental lung research 4 32410473
2017 RAI3 knockdown promotes adipogenic differentiation of human adipose-derived stem cells by decreasing β-catenin levels. Biochemical and biophysical research communications 4 28870805
2025 GPRC5A modulates resistance to temozolomide in glioblastoma through glycolytic reprogramming. International journal of biological macromolecules 3 40744179
2025 Engineered NK92 cell-derived exosomes inhibit ovarian cancer progression by degrading GPRC5A. Frontiers in immunology 3 41306963
2020 MicroRNA-342-5p protects against myocardial ischemia-reperfusion injury by targeting the GPRC5A pathway. Die Pharmazie 3 32539924
2025 Integrating single-cell RNA sequencing and spatial transcriptomics to reveal the Glycolysis-related gene GPRC5A as a potential biomarker for gastric cancer by machine learning. International journal of biological macromolecules 2 40865843
2023 GPRC5A regulates proliferation and oxidative stress by inhibiting the STAT3/Socs3/c-MYC pathway in hepatocellular carcinoma. Journal of clinical biochemistry and nutrition 2 37534091
2020 Identification and characterization of human PEIG-1/GPRC5A as a 12-O-tetradecanoyl phorbol-13-acetate (TPA) and PKC-induced gene. Archives of biochemistry and biophysics 2 32339486
2025 Vitamin D and Retinoic Acid Require Protein Kinase C Activity and Reactive Oxygen Species as Opposing Signals Regulating PEIG-1/GPRC5A Expression in Caco-2 and T84 Colon Carcinoma Cells. Biomolecules 1 40427604
2025 Galectin-3 Mediated Endocytosis of the Orphan G-Protein-Coupled Receptor GPRC5A. Cells 1 41090797
2024 Deciphering the molecular regulatory of RAB32/GPRC5A axis in chronic obstructive pulmonary disease. Respiratory research 1 38448858
2023 RAI3 expression is not associated with clinical outcomes of patients with non-small cell lung cancer. Journal of cancer research and clinical oncology 1 36781501
2019 High levels of RAI3 expression is linked to shortened survival in esophageal cancer patients. Experimental and molecular pathology 1 30707896
2025 A noncanonical-GPRC5A signaling regulates keratinocyte adhesion and migration by nuclear translocation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 39812615
2025 GPRC5A+ myCAFs promote ESCC progression via TGF-β-induced fibroblast activation and ANXA1-mediated M2 macrophage polarization. International immunopharmacology 0 41082840
2024 Circ_0007351 Exerts an Oncogenic Role In Colorectal Cancer Depending on the Modulation of the miR-5195-3p/GPRC5A Cascade. Molecular biotechnology 0 38386274
2024 Influence of GPRC5A-Regulated ABCB1 Expression on Lung Adenocarcinoma Proliferation. Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih 0 38426412
2024 GPRC5A promotes paclitaxel resistance and glucose content in NSCLC. Anti-cancer drugs 0 38602327
2023 Circular RNA Gprc5a Promotes HCC Progression by Activating YAP1/TEAD1 Signalling Pathway by Sponging miR-1283 [Retraction]. OncoTargets and therapy 0 37587912

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