GPR107

GPR107 is a type III integral membrane protein with a C-terminal seven-transmembrane (LUSTR) domain and a long luminal/extracellular region that localizes to the trans-Golgi network and is essential for retrograde vesicular transport (PMID:25031321, PMID:17454009). In the secretory pathway it is proteolytically cleaved by furin, with the two resulting fragments held together by a disulfide bond whose disruption impairs function; the N-terminal region is critical for its activity in Pseudomonas exotoxin A intoxication (PMID:25031321). Beyond Golgi-based transport, GPR107 supports clathrin- and retromer-dependent receptor recycling: its loss reduces transferrin internalization and LRP1 cargo uptake, confers toxin resistance, and it associates with clathrin and the retromer subunit VPS35 (PMID:24849652). GPR107 also functions as a receptor for the peptide neuronostatin, which binds it directly and drives cAMP-independent PKA activation that controls downstream outputs including proglucagon expression, neuronal survival and neurite outgrowth, and mitochondrial energetics (PMID:26561648, PMID:39048031). GPR107 undergoes phosphorylation-dependent Golgi retention, with Tyr315 required for maintaining mitochondrial protein expression and ROS regulation during glucose metabolism (PMID:42208758). In breast cancer it promotes invasion by mediating clathrin-dependent endocytosis of collagen IV, suppressing COL4 transcription, and activating an ERK/STAT3 axis through β-arrestin to upregulate MMP2 (PMID:41073571). Loss of Gpr107 in mice is embryonic lethal (PMID:24849652).

1. 2007 Medium

   Establishing the primary molecular identity of GPR107 was needed before any functional role could be assigned; cloning defined it as a multi-domain seven-transmembrane protein.

   Evidence cDNA cloning, sequence and genomic mapping of human GPR107 from lung tissue

   PMID:17454009

   Open questions at the time

   • No functional or signaling role assigned
   • No subcellular localization determined
   • No ligand identified
2. 2012 Medium

   Whether GPR107 acts as a functional receptor was unknown; loss-of-function in cells and brain showed it is required for neuronostatin-induced signaling and cardiovascular responses.

   Evidence siRNA knockdown in KATOIII cells and intracerebroventricular siRNA in rats with MAP/baroreflex readouts

   PMID:22933024

   Open questions at the time

   • No direct ligand binding demonstrated
   • Downstream signaling cascade not defined
   • Single lab
3. 2014 High

   The cell-biological function of GPR107 was undefined; a genome-wide screen placed it in TGN retrograde transport and revealed its furin cleavage and disulfide-linked architecture.

   Evidence Genome-wide haploid screen, CRISPR editing, localization, furin cleavage and disulfide disruption assays, domain deletion in toxin intoxication

   PMID:25031321

   Open questions at the time

   • Molecular mechanism of retrograde transport role unresolved
   • Direct transport cargoes not enumerated
   • No structure of cleaved/disulfide-linked form
4. 2014 Medium

   Extending function to endocytic recycling and organismal essentiality, knockout and proteomics linked GPR107 to clathrin/VPS35-dependent receptor recycling.

   Evidence Gpr107 knockout mouse (embryonic lethal), transferrin/LDL uptake and toxin assays, colocalization and proteomic VPS35/clathrin association

   PMID:24849652

   Open questions at the time

   • Clathrin/VPS35 association from colocalization/proteomics without reconstitution
   • Direct versus indirect interaction unresolved
   • Cause of embryonic lethality not mechanistically defined
5. 2015 Medium

   To define where neuronostatin signaling operates, GPR107 was placed upstream of cAMP-independent PKA activation in pancreatic α-cells.

   Evidence GPR107 knockdown, PKA phosphorylation and proglucagon mRNA assays, colocalization in rodent and human islets

   PMID:26561648

   Open questions at the time

   • Mechanism coupling GPR107 to PKA without cAMP not defined
   • No direct binding assay
   • Single lab
6. 2024 Medium

   Whether neuronostatin binds GPR107 directly was unresolved; structural analyses confirmed direct binding and extended function to neuronal survival and mitochondrial metabolism.

   Evidence Structural binding analyses, primary neurons, knockout cells, PKA, ROS and mitochondrial membrane potential assays

   PMID:39048031

   Open questions at the time

   • Atomic-resolution receptor structure not reported
   • Link between TGN localization and surface signaling unclear
   • Single lab
7. 2025 Medium

   A disease-relevant effector role was unknown; GPR107 was shown to drive breast cancer invasion via collagen IV endocytosis and β-arrestin/ERK/STAT3-dependent MMP2 upregulation.

   Evidence Loss- and gain-of-function in breast cancer cells, endocytosis assays, MMP2/COL4 analysis, ERK/STAT3 and β-arrestin pathway studies

   PMID:41073571

   Open questions at the time

   • β-arrestin recruitment to GPR107 not biochemically reconstituted
   • In vivo metastasis contribution limited
   • No independent replication
8. 2026 Medium

   How GPR107 trafficking is regulated and coupled to metabolism was open; phosphorylation-dependent Golgi retention with Tyr315 was identified as controlling mitochondrial protein expression and ROS.

   Evidence Cyclic neuronostatin agonist pharmacology, phosphorylation assays, Tyr315 mutagenesis, Golgi retention and mitochondrial assays in zebrafish and mice

   PMID:42208758

   Open questions at the time

   • Kinase responsible for Tyr315 phosphorylation not identified
   • Mechanistic link from Golgi retention to mitochondrial outputs unclear
   • Single lab

• How GPR107's roles in TGN retrograde transport, endocytic recycling, and neuronostatin-evoked PKA signaling are mechanistically integrated within a single protein remains unresolved.
• No structural model reconciling transport and receptor functions
• Kinase/effector coupling to cAMP-independent PKA undefined
• Direct biochemical demonstration of clathrin/retromer interaction lacking