VSIG2

VSIG2 is a type I transmembrane immunoglobulin superfamily (IgSF) member containing one variable-type and one C2-type Ig domain, a transmembrane segment, and a cytoplasmic tail, belonging to a conserved vertebrate IgSF subfamily that includes the A33 antigen and CAR (PMID:9862345). In pancreatic ductal adenocarcinoma, VSIG2 functions as an intracellular scaffold that simultaneously binds LAMTOR2 and mTOR, stabilizing their interaction to enhance mTOR phosphorylation and promote tumor cell proliferation and invasion (PMID:37626304). In gastric cancer, VSIG2 suppresses tumor progression by competing with the E3 ligase FBXW10 for binding to ANXA2, thereby promoting FBXW10-mediated K63 polyubiquitination-dependent membrane localization of ANXA2 and consequent inactivation of NF-κB signaling (PMID:41185558). On the surface of antigen-presenting cells, VSIG2 serves as an immunosuppressive ligand that binds Nectin-2 to inhibit T cell activation through the STAT1/IRF1/GBP2 pathway, and blockade of this axis with anti-VSIG2 antibodies inhibits pancreatic cancer growth in vivo (PMID:41350674).

1. 1998 Medium

   Cloning of human CTH (VSIG2) established it as a new IgSF member with a distinctive V+C2 domain architecture encoded by half-domain exons, placing it in a conserved vertebrate subfamily alongside A33 and CAR and raising questions about its function outside lymphocytes.

   Evidence cDNA cloning, exon mapping, and comparative sequence analysis across species

   PMID:9862345

   Open questions at the time

   • No functional role assigned; expression pattern outside lymphocytes not characterized
   • No binding partner or ligand identified
   • No loss-of-function data
2. 2003 Low

   A large-scale secreted protein discovery screen confirmed VSIG2 as a signal-peptide-bearing cell-surface protein, consistent with receptor or ligand function but without functional characterization.

   Evidence Signal sequence trap in yeast and computational prediction from human cDNA libraries

   PMID:12975309

   Open questions at the time

   • No functional follow-up; identification was part of a high-throughput screen without individual validation
   • Subcellular localization not directly imaged
   • No interacting partners tested
3. 2023 Medium

   The first mechanistic role for VSIG2 was defined in PDAC, where it was shown to scaffold a LAMTOR2–mTOR ternary complex, enhancing mTOR phosphorylation and driving tumor cell proliferation and invasion — revealing VSIG2 as a signaling scaffold rather than solely a cell-surface receptor.

   Evidence Mass spectrometry interactome, reciprocal co-immunoprecipitation, immunofluorescence co-localization, gain/loss-of-function assays, and xenograft models in PDAC cells

   PMID:37626304

   Open questions at the time

   • Single-lab study; the VSIG2–LAMTOR2–mTOR interaction has not been reconstituted with purified components
   • Which domain of VSIG2 mediates LAMTOR2 versus mTOR binding is unknown
   • Contribution of the extracellular Ig domains versus the cytoplasmic tail to scaffold function not dissected
4. 2025 Medium

   Two studies expanded VSIG2's functional repertoire in opposite directions: as an immunosuppressive ligand binding Nectin-2 to inhibit T cells via STAT1/IRF1/GBP2, and as a tumor suppressor in gastric cancer that competes with FBXW10 for ANXA2, promoting K63-ubiquitination-dependent ANXA2 membrane localization to inactivate NF-κB.

   Evidence Binding specificity assays excluding PD-1/CTLA-4, T cell proliferation assays, EAE and tumor models (immunosuppression study); Co-IP, ubiquitination assays with K63 linkage specificity, xenograft and metastasis models (gastric cancer study)

   PMID:41185558 PMID:41350674

   Open questions at the time

   • Both studies are from single laboratories and await independent replication
   • How VSIG2 simultaneously acts as an extracellular Nectin-2 ligand and an intracellular ANXA2/LAMTOR2 scaffold in the same cell is unresolved
   • Structural basis of the VSIG2–Nectin-2 interaction is undetermined
   • Context-dependent tumor-promoting (PDAC) versus tumor-suppressive (GC) roles are not reconciled mechanistically

• Key open questions include which domain(s) mediate each interaction, how tissue context determines the oncogenic versus tumor-suppressive output, and whether the immune-checkpoint and intracellular scaffold functions operate simultaneously or are mutually exclusive on the same cell.
• No crystal or cryo-EM structure available for VSIG2 or its complexes
• No genetic mouse model to assess physiological non-redundant function
• Relationship between mTOR-scaffolding function and Nectin-2-binding function has not been tested