Affinage

GPR107

Protein GPR107 · UniProt Q5VW38

Length
600 aa
Mass
67.0 kDa
Annotated
2026-04-28
9 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR107 is a LUSTR-family integral membrane protein that functions in vesicular trafficking and peptide receptor signaling at the trans-Golgi network. It localizes to the trans-Golgi network, is proteolytically processed by furin into disulfide-linked fragments, and associates with clathrin and the retromer component VPS35 to mediate retrograde transport and receptor recycling; genetic ablation in mice causes embryonic lethality with defects in endocytic receptor complexes and impaired cargo internalization (PMID:25031321, PMID:24849652). GPR107 also serves as the functional receptor for neuronostatin, transducing signals through a cAMP-independent PKA phosphorylation pathway that regulates cardiovascular tone, pancreatic proglucagon expression, and neuronal survival (PMID:22933024, PMID:26561648, PMID:39048031). In breast cancer cells, GPR107 promotes invasion by activating ERK/STAT3 signaling through β-arrestin, driving MMP2 upregulation and collagen IV degradation (PMID:41073571).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2007 Medium

    Cloning of GPR107 established its domain architecture — a long extracellular domain followed by a seven-transmembrane LUSTR domain distinct from classical GPCRs — defining the gene product as a novel class of membrane protein.

    Evidence cDNA cloning and sequence analysis from human lung

    PMID:17454009

    Open questions at the time
    • No ligand or cellular function identified at this stage
    • LUSTR domain function not characterized beyond sequence homology
    • Protein expression and localization not experimentally determined
  2. 2012 Medium

    Identification of GPR107 as a candidate receptor for neuronostatin answered the question of what ligand activates this orphan receptor and linked it to cardiovascular regulation via PKA signaling.

    Evidence siRNA knockdown in KATOIII cells abolished NST signaling; intracerebroventricular siRNA in rats blocked NST-induced cardiovascular responses

    PMID:22933024

    Open questions at the time
    • Direct physical binding of NST to GPR107 not demonstrated at this stage
    • Mechanism of cAMP-independent PKA activation unclear
    • Single-lab finding without independent replication
  3. 2014 High

    Two independent studies converged to define GPR107's core cell-biological role: it localizes to the trans-Golgi network, undergoes furin-mediated cleavage held by a disulfide bond, and is essential for retrograde transport and receptor recycling, as shown by its association with clathrin and VPS35 and by embryonic lethality upon knockout.

    Evidence Genome-wide haploid screen with CRISPR validation, furin cleavage and mutagenesis assays, toxin intoxication (PMID:25031321); Gpr107 knockout mouse, transferrin/LRP1 uptake assays, co-purification with clathrin and VPS35 (PMID:24849652)

    PMID:24849652 PMID:25031321

    Open questions at the time
    • Structural basis of GPR107-retromer and GPR107-clathrin interactions not resolved
    • Specific cargo repertoire beyond cubilin/LRP1/transferrin receptor unknown
    • Relationship between furin cleavage and trafficking function not fully delineated
  4. 2015 Medium

    Demonstrating that GPR107 mediates neuronostatin-induced PKA phosphorylation and proglucagon expression in pancreatic α-cells extended GPR107's receptor function beyond the cardiovascular system to endocrine regulation.

    Evidence GPR107 knockdown in α-cells abolished NST-induced PKA phosphorylation and proglucagon mRNA elevation; immunofluorescence colocalization of GPR107 and NST in mouse and human α-cells

    PMID:26561648

    Open questions at the time
    • Single-lab replication of the NST-GPR107 axis
    • Downstream effectors between PKA and proglucagon transcription not identified
    • Whether GPR107's trafficking function contributes to its signaling function is unknown
  5. 2018 Medium

    Discovery that lncGPR107 recruits the SRCAP chromatin-remodeling complex to activate GPR107 transcription in liver tumor-initiating cells revealed how GPR107 expression is epigenetically regulated in cancer.

    Evidence RNA pulldown, RIP, ChIP, and oncosphere/tumor initiation assays in liver TICs

    PMID:29925408

    Open questions at the time
    • Functional consequence of elevated GPR107 in liver TICs not mechanistically dissected
    • Whether SRCAP-mediated activation is specific to liver cancer or broadly relevant is unknown
    • Single-lab finding
  6. 2024 Medium

    Structural binding analyses demonstrating direct NST-GPR107 interaction, together with evidence that GPR107 mediates NST-dependent neuronal survival, mitochondrial function, and neuroprotection against Aβ, solidified GPR107 as a bona fide NST receptor with neuroprotective roles.

    Evidence Structural binding analyses; primary neuronal cultures and GPR107 knockout cells; mitochondrial assays; in vivo NST administration in APP/PS1 mice

    PMID:39048031

    Open questions at the time
    • High-resolution co-structure of NST-GPR107 complex not yet reported
    • Mechanism coupling GPR107/PKA to mitochondrial function not resolved
    • Single-lab study
  7. 2025 Medium

    Showing that GPR107 activates ERK/STAT3 via β-arrestin to promote MMP2-dependent collagen IV degradation and breast cancer metastasis revealed a signaling mode distinct from the PKA pathway and a pro-invasive oncogenic function.

    Evidence Loss/gain-of-function in breast cancer cells; clathrin-mediated endocytosis, ERK/STAT3 pathway analysis, β-arrestin interaction studies, invasion/metastasis assays

    PMID:41073571

    Open questions at the time
    • No independent replication of the β-arrestin–ERK/STAT3 axis
    • Ligand that triggers GPR107/β-arrestin signaling in cancer not identified
    • Relationship between GPR107's trafficking and signaling functions in cancer unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of GPR107 in complex with NST, how GPR107's dual roles in vesicular trafficking and receptor signaling are mechanistically integrated, and the identity of additional ligands or cargoes.
  • No high-resolution structure of GPR107 or NST-GPR107 complex available
  • Mechanistic link between trafficking function (retromer/clathrin) and signaling function (PKA, ERK/STAT3) unresolved
  • Full cargo and ligand repertoire unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 3
Partners
ARRB1CLTCFURINVPS35

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 GPR107 is a candidate receptor for neuronostatin (NST): siRNA knockdown of GPR107 in KATOIII cells abolished neuronostatin-induced signaling, and intracerebroventricular GPR107 siRNA in rats blocked NST-induced increases in mean arterial pressure and blunted baroreflex sensitivity, indicating GPR107 mediates NST cardiovascular signaling via a PKA-dependent mechanism. siRNA knockdown in KATOIII cells; intracerebroventricular siRNA injection in rats with physiological readouts (MAP, baroreflex) American journal of physiology. Regulatory, integrative and comparative physiology Medium 22933024
2014 GPR107 localizes to the trans-Golgi network, is cleaved by the endoprotease furin, and the two resulting fragments are held together by a disulfide bond; disruption of this disulfide association impairs GPR107 function. GPR107 is essential for retrograde transport and intoxication by Pseudomonas aeruginosa exotoxin A, identified via a genome-wide genetic screen confirmed by CRISPR/Cas9 editing. Genome-wide haploid genetic screen; CRISPR/Cas9 knockout; subcellular localization (Golgi markers); furin cleavage assay; disulfide bond disruption mutagenesis; toxin intoxication assay The Journal of biological chemistry High 25031321
2014 Deletion of Gpr107 in mice causes embryonic lethality associated with reduced cubilin transcript abundance and defects in the cubilin-megalin endocytic complex; Gpr107-null fibroblasts show reduced transferrin internalization, decreased LRP1 cargo uptake, and resistance to toxins. Proteomic and colocalization analyses indicate GPR107 associates with clathrin and the retromer protein VPS35, suggesting a role in recycling receptors from endocytic compartments back to the plasma membrane. Gpr107 knockout mouse (embryonic lethal phenotype); transferrin/LDL internalization assays; toxin resistance assay; colocalization microscopy; proteomic analysis (co-purification with clathrin and VPS35) Journal of cell science High 24849652
2007 Human GPR107 was cloned from lung and shown to encode a 552-residue protein with an N-terminal hydrophobic signal peptide, a long extracellular domain, and a C-terminal seven-transmembrane (LUSTR) domain, placing it in a novel LUSTR family distinct from classical GPCRs; the gene spans 86.4 kb at 9q34.2-3 and contains 18 exons. cDNA cloning, sequence analysis, genomic mapping DNA sequence : the journal of DNA sequencing and mapping Medium 17454009
2015 GPR107 is abundantly expressed in pancreatic α-cells; neuronostatin acting through GPR107 increases cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation. Knockdown of GPR107 in α-cells abolishes NST-induced PKA phosphorylation and proglucagon mRNA elevation. GPR107 and NST colocalize in mouse and human pancreatic α-cells. GPR107 knockdown in pancreatic α-cells; PKA phosphorylation assay; proglucagon mRNA quantification; immunofluorescence colocalization American journal of physiology. Regulatory, integrative and comparative physiology Medium 26561648
2018 Expression of GPR107 in liver tumor-initiating cells (TICs) is transcriptionally activated by the lncRNA lncGPR107, which recruits the SRCAP chromatin-remodeling complex to the GPR107 promoter; depletion of lncGPR107 reduces SRCAP binding to the GPR107 promoter and suppresses GPR107 expression and TIC self-renewal. RNA pulldown, RNA immunoprecipitation, ChIP, FACS sorting, oncosphere formation assay, tumor initiation assay, western blot, double FISH Journal of experimental & clinical cancer research : CR Medium 29925408
2024 NST directly binds GPR107 (structural analyses); GPR107 is primarily expressed in neurons; NST modulates neuronal survival and neurite outgrowth in response to Aβ via GPR107; NST regulates mitochondrial function and ATP levels through a GPR107/PKA signaling pathway. Structural binding analyses; primary neuronal cultures; GPR107 knockout cells; mitochondrial membrane potential and ROS assays; PKA signaling readouts; intracerebroventricular NST administration in APP/PS1 mice Neuropharmacology Medium 39048031
2025 GPR107 promotes breast cancer invasion and metastasis by mediating clathrin-dependent endocytosis of collagen IV (COL4) from the ECM, upregulating MMP2 production to degrade COL4, and suppressing COL4 gene transcription; mechanistically, GPR107 activates the ERK/STAT3 pathway through β-arrestin, increasing MMP2 expression and reducing COL4. Loss-of-function/gain-of-function in breast cancer cells; invasion/metastasis assays; clathrin-mediated endocytosis assay; ERK/STAT3 pathway analysis; MMP2 and COL4 quantification; β-arrestin interaction studies Cancer gene therapy Medium 41073571

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107. American journal of physiology. Regulatory, integrative and comparative physiology 51 22933024
2014 GPR107, a G-protein-coupled receptor essential for intoxication by Pseudomonas aeruginosa exotoxin A, localizes to the Golgi and is cleaved by furin. The Journal of biological chemistry 43 25031321
2015 Neuronostatin acts via GPR107 to increase cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation in pancreatic α-cells. American journal of physiology. Regulatory, integrative and comparative physiology 33 26561648
2007 Human GPR107 and murine Gpr108 are members of the LUSTR family of proteins found in both plants and animals, having similar topology to G-protein coupled receptors. DNA sequence : the journal of DNA sequencing and mapping 27 17454009
2014 Deficits in receptor-mediated endocytosis and recycling in cells from mice with Gpr107 locus disruption. Journal of cell science 22 24849652
2018 LncGPR107 drives the self-renewal of liver tumor initiating cells and liver tumorigenesis through GPR107-dependent manner. Journal of experimental & clinical cancer research : CR 11 29925408
2020 Changes in expression of orphan receptors GPR99 and GPR107 during the development and establishment of hypertension in spontaneously hypertensive rats. Journal of receptor and signal transduction research 6 33121311
2024 Neuronostatin regulates neuronal function and energetic metabolism in Alzheimer's disease in a GPR107-dependent manner. Neuropharmacology 2 39048031
2025 GPR107: A key driver of breast cancer invasion and metastasis through collagen IV modulation. Cancer gene therapy 0 41073571