PTGFRN

PTGFRN is a transmembrane Ig-superfamily protein that serves as a near-stoichiometric organizing partner of the tetraspanins CD9 and CD81, with essentially all cell-surface PTGFRN found in discrete CD81/CD9-associated complexes distinct from integrin-containing tetraspanin assemblies (PMID:11087758). Cryo-EM resolves the structural basis of this organization: two PTGFRN molecules dimerize through their ectodomains while each engages a CD9 transmembrane helix, generating a conformationally flexible heterotetramer that provides a concatenation model for tetraspanin-enriched microdomain formation (PMID:32958604). Through a stretch of basic residues in its cytoplasmic domain, PTGFRN directly recruits ERM (ezrin-radixin-moesin) proteins, linking these microdomains to the actin cytoskeleton and governing cell motility and polarity (PMID:16690612). PTGFRN can also self-associate into tetraspanin-independent cis-oligomers and is heavily N-glycosylated across multiple surface isoforms (PMID:19703604, PMID:17960739). Functionally, it acts as a negative regulator of the prostaglandin F2α (FP) receptor by reducing receptor number in a non-competitive manner (PMID:8804121). In cancer, PTGFRN supports oncogenic signaling: its loss destabilizes PI3K p110β and lowers AKT phosphorylation (PMID:31377205), reduces ERK/AKT/mTOR signaling and stemness factors in glioma (PMID:35690717), and stabilizes STAT3 to drive BCAT1-dependent branched-chain amino acid metabolism in lung cancer (PMID:41130302). Truncated PTGFRN that retains CD81-binding depletes tetraspanins and PTGFRN from the endothelial surface and inhibits VEGF-dependent angiogenesis and tumor growth (PMID:21863033).

1. 1996 Medium

   Established the first functional role for PTGFRN by showing it suppresses prostaglandin F2α receptor signaling, defining it as a receptor-modulating membrane protein rather than a passive surface antigen.

   Evidence cDNA transfection in COS cells with radioligand binding and Scatchard analysis of FP receptor

   PMID:8804121

   Open questions at the time

   • Mechanism by which PTGFRN reduces FP receptor number is undefined
   • No structural or interaction data linking PTGFRN to the FP receptor
   • Single lab
2. 2000 High

   Resolved which surface complexes PTGFRN occupies, showing it is an obligate, high-stoichiometry partner of CD9/CD81 in complexes separable from integrin-tetraspanin assemblies.

   Evidence Co-IP, immunodepletion, and gel permeation chromatography across multiple cell types

   PMID:11087758

   Open questions at the time

   • Did not define the molecular interface
   • Functional consequence of the association not tested
3. 2006 High

   Connected the tetraspanin microdomain to the cytoskeleton by demonstrating PTGFRN directly recruits ERM proteins through a basic cytoplasmic motif, providing a mechanistic basis for its role in motility and polarity.

   Evidence GST pulldown with cytoplasmic fusion proteins, co-IP, confocal colocalization, dominant-negative moesin and siRNA

   PMID:16690612

   Open questions at the time

   • Quantitative contribution to actin linkage versus other ERM recruiters unknown
   • Regulation of the ERM interaction not addressed
4. 2007 Medium

   Characterized PTGFRN as extensively N-glycosylated and exosome-targeted, indicating post-translational diversity and a route into secreted vesicles partly independent of tetraspanins.

   Evidence MS-based glycan structural analysis and exosome fractionation with co-IP after TPA treatment

   PMID:17407154 PMID:17960739

   Open questions at the time

   • Functional role of specific glycoforms not tested
   • Determinants of exosomal sorting unresolved
5. 2009 Medium

   Mapped the CD81 interaction to transmembrane regions and revealed tetraspanin-independent cis-oligomerization, refining how PTGFRN assembles within and beyond the tetraspanin web.

   Evidence Chimeric molecule analysis with infection assays; in situ cross-linking with LC-MS/MS

   PMID:19703604 PMID:19762465

   Open questions at the time

   • Stoichiometry of oligomers not defined at the time
   • Link between Plasmodium restriction and oligomerization unexplored
6. 2011 Medium

   Demonstrated therapeutic-relevant disruption: a CD81-binding truncated PTGFRN depletes tetraspanins from endothelium and blocks angiogenesis, implicating the complex in vascular and tumor biology.

   Evidence Co-precipitation, flow cytometry, in vitro angiogenesis assays, and in vivo tumor xenografts

   PMID:21863033

   Open questions at the time

   • Direct signaling pathway downstream of complex depletion not defined
   • IFITM5-induced CD9 dissociation finding rests on a single co-IP
7. 2020 High

   Provided the atomic-level model for tetraspanin microdomain assembly, showing PTGFRN ectodomain dimers bridge two CD9 molecules in a flexible tetramer that can concatenate.

   Evidence Cryo-EM of the CD9–EWI-F complex with crystallographic validation of CD9 loop–nanobody binding

   PMID:32958604

   Open questions at the time

   • Structure with CD81 not determined
   • Cytoplasmic ERM-binding region not resolved in the structure
8. 2025 Medium

   Extended PTGFRN into oncogenic signaling, showing it stabilizes signaling effectors (p110β, STAT3) and drives downstream pathways including BCAT1-mediated amino acid metabolism, ERK/AKT/mTOR, and stemness programs.

   Evidence shRNA/siRNA knockdown with western blot, nuclear fractionation, ChIP of STAT3 on BCAT1 promoter, and metabolic assays across GBM, glioma, and NSCLC models

   PMID:31377205 PMID:35690717 PMID:41130302

   Open questions at the time

   • Direct biochemical mechanism linking surface PTGFRN to intracellular p110β/STAT3 stabilization unclear
   • Whether these effects depend on tetraspanin association untested
   • Each readout from a single lab

• How PTGFRN's structurally defined membrane-organizing role mechanistically connects to its reported intracellular signaling effects (p110β, STAT3, ERK/mTOR) and to direct binding of Integrin β1/E-Cadherin remains unresolved.
• Integrin β1 and E-Cadherin binding rest on single unreciprocated co-IPs
• No mechanism links transmembrane scaffolding to cytoplasmic signaling stabilization
• Autophagy and innate-immune effects defined only by proteomic profiling