VSIG2

VSIG2 is an immunoglobulin-superfamily cell-surface protein that exerts context-dependent, tissue-specific roles in cancer progression and immune regulation (PMID:37626304, PMID:41350674, PMID:41185558). As an immunosuppressive ligand on activated antigen-presenting cells, VSIG2 binds Nectin-2 — but not PD-1 or CTLA-4 — and strongly inhibits T cell activation and proliferation through the STAT1/IRF1/GBP2 signaling axis; a VSIG2-Ig fusion alleviated experimental autoimmune encephalomyelitis, while anti-VSIG2 antibodies suppressed pancreatic cancer growth in vivo (PMID:41350674). In pancreatic ductal adenocarcinoma cells, VSIG2 acts intracellularly as a scaffold that simultaneously binds LAMTOR2 and mTOR, enhancing their interaction and driving mTOR phosphorylation and downstream signaling to promote proliferation, invasion, and migration (PMID:37626304). In gastric cancer, by contrast, VSIG2 is tumor-suppressive: it directly binds ANXA2 at the membrane and competes with FBXW10, promoting FBXW10-mediated K63 polyubiquitination and membrane localization of ANXA2, thereby inactivating NF-κB and restraining proliferation and migration (PMID:41185558). The structural basis of these interactions and how a single protein partitions between surface ligand and intracellular scaffold functions have not been characterized in the available corpus.

1. 2023 Medium

   Established the first molecular mechanism for VSIG2 in cancer by identifying it as an intracellular scaffold linking LAMTOR2 to mTOR activation.

   Evidence Mass spectrometry, reciprocal co-immunoprecipitation, immunofluorescence, functional assays and xenografts with VSIG2 overexpression/knockdown in pancreatic ductal adenocarcinoma cells

   PMID:37626304

   Open questions at the time

   • No structural definition of the LAMTOR2/mTOR-bridging interface
   • Whether the scaffold function operates at a specific subcellular compartment is not resolved
   • Single lab, no independent replication
2. 2025 Medium

   Identified VSIG2 as a tumor-suppressive partner of ANXA2 in gastric cancer, defining a competitive-binding/ubiquitination mechanism opposite to its pancreatic role.

   Evidence Reciprocal co-immunoprecipitation, ubiquitination assays, immunofluorescence, in vitro proliferation/migration assays and subcutaneous plus liver-metastasis mouse models in gastric cancer cells

   PMID:41185558

   Open questions at the time

   • Mechanism by which K63-ubiquitinated ANXA2 inactivates NF-κB not detailed
   • Reason for opposite tumor role versus pancreatic cancer unexplained
   • Single lab, no independent replication
3. 2025 Medium

   Defined VSIG2 as a cell-surface immunosuppressive ligand, identifying Nectin-2 as its receptor and the STAT1/IRF1/GBP2 axis as the downstream T cell pathway.

   Evidence Ligand-receptor binding assays, T cell activation/proliferation assays, in vivo EAE and pancreatic cancer models, pathway analysis

   PMID:41350674

   Open questions at the time

   • Structural basis of VSIG2-Nectin-2 binding not determined
   • How surface ligand activity reconciles with reported intracellular scaffold function is unclear
   • Single lab, no independent replication

• How VSIG2 partitions between cell-surface immune-ligand and intracellular scaffold/adaptor functions, and what determines its opposing pro- versus anti-tumor roles across tissues, remains unresolved.
• No structural model for any VSIG2 interaction
• No reconciliation of surface versus intracellular localization across contexts
• Determinants of context-dependent tumor outcome unknown