SUSD2

SUSD2 is a type I transmembrane glycoprotein that functions as a multifunctional adhesion and signaling molecule at the plasma membrane, integrating immune regulation, cell-matrix interactions, and intercellular communication across diverse tissue contexts. SUSD2 reaches the cell surface through obligate proteolytic cleavage at a GDPH motif by a serine protease, with inter-fragment disulfide bonds maintaining the mature heterodimer required for surface presentation of itself and its binding partner galectin-1 (PMID:31387209, PMID:23131994). In the immune compartment, SUSD2 suppresses CD8+ T cell effector function by engaging IL-2Rα via its sushi domain to block IL-2 signaling (PMID:36266363), promotes macrophage recruitment and M2 polarization through MCP-1/CCL2 secretion (PMID:28475599), and serves as the receptor for the cytokine CSBF, competing with TRAF6/TNFR1 for ACT1 binding to inhibit IL-17A and TNF-α inflammatory signaling (PMID:40804449). SUSD2 also engages integrin β1 to activate FAK-mediated focal adhesion formation and cell motility (PMID:41513453), localizes to excitatory synapses in neurons where it regulates synapse number and neurite morphology (PMID:25724483), and in intestinal epithelia organizes innexin gap junction clustering at cell-cell contacts (PMID:37067458).

1. 2007 Medium

   Establishing SUSD2 as a surface-oriented adhesion-class transmembrane protein with tumor-suppressive properties answered the foundational question of its topology and cellular role.

   Evidence Confocal microscopy of tagged SUSD2 plus functional assays (clonogenicity, migration, invasion) in cancer cell lines

   PMID:17428258

   Open questions at the time

   • No endogenous binding partners identified
   • Tumor-suppressive phenotype shown only in vitro
   • Adhesion ligand not determined
2. 2007 Medium

   Mutagenesis of the vWD domain GLLG motif revealed that correct membrane topology is critical for SUSD2 function, as topological inversion triggered caspase-dependent apoptosis via Akt dephosphorylation—separating a gain-of-function toxicity from normal SUSD2 biology.

   Evidence Site-directed mutagenesis of GLLG591–594 with caspase-3/9 activity assays and Akt phosphorylation blots

   PMID:17428257

   Open questions at the time

   • Mechanism of topology sensing unknown
   • Relevance of GLLG mutant to physiological processing unclear
3. 2012 Medium

   Discovery that SUSD2 binds galectin-1 and is required for its surface presentation identified the first mechanism through which SUSD2 could mediate immune evasion—galectin-1-dependent T cell apoptosis.

   Evidence Co-immunoprecipitation of SUSD2–Gal-1, surface flow cytometry, Jurkat T cell co-culture apoptosis assay

   PMID:23131994

   Open questions at the time

   • Binding interface between SUSD2 and Gal-1 not mapped
   • In vivo immune evasion not demonstrated at this stage
4. 2015 Medium

   Demonstration that Susd2 localizes to excitatory synapses and regulates synapse number and neurite morphology expanded its functional scope beyond cancer to neuronal development.

   Evidence shRNA knockdown in rat hippocampal neurons with confocal synapse counting and morphometric analysis

   PMID:25724483

   Open questions at the time

   • Synaptic binding partner not identified
   • Mechanism of selective excitatory synapse association unknown
   • No in vivo knockout behavioral phenotype reported
5. 2017 Medium

   SUSD2 was placed in the tumor immune microenvironment by showing it drives MCP-1/CCL2 secretion to recruit and polarize macrophages to an M2 phenotype, linking SUSD2 to paracrine immune modulation beyond direct T cell effects.

   Evidence SUSD2 knockdown/overexpression with ELISA, macrophage co-culture, syngeneic mouse tumor model

   PMID:28475599

   Open questions at the time

   • Signaling pathway from SUSD2 to MCP-1 transcription not defined
   • Macrophage polarization not confirmed in patient tumors
6. 2017 Medium

   Placing SUSD2 downstream of TGFβ/SMAD2/3 signaling and showing that its loss activates SMAD2/3 and senescence revealed a reciprocal regulatory loop between SUSD2 and TGFβ pathway components.

   Evidence TGFβ treatment, siRNA silencing, SMAD2/3 phosphorylation blots, β-galactosidase senescence staining in endometrial cancer cells

   PMID:28841682

   Open questions at the time

   • Whether SUSD2 directly modulates SMAD2/3 or acts indirectly is unclear
   • Senescence phenotype not validated in vivo
7. 2018 Medium

   Epistasis experiments positioned SUSD2 downstream of Notch3 and upstream of EpCAM in an EMT signaling cascade in ovarian cancer, providing a defined signaling hierarchy.

   Evidence SUSD2 overexpression/knockdown with EpCAM siRNA rescue, EMT marker blots, xenograft

   PMID:29305171

   Open questions at the time

   • Direct physical interaction between SUSD2 and EpCAM not tested
   • Mechanism by which SUSD2 regulates EpCAM expression unknown
8. 2019 High

   The discovery that SUSD2 undergoes obligate serine protease-mediated cleavage at its GDPH motif, requiring disulfide-linked fragment retention, resolved how the protein matures and explained why it must be processed to reach the plasma membrane and present galectin-1.

   Evidence GDPH-deletion and cysteine mutagenesis, Pefabloc SC protease inhibition, cell surface flow cytometry

   PMID:31387209

   Open questions at the time

   • Identity of the cleaving serine protease not determined
   • Structural basis of fragment reassociation not resolved
9. 2022 High

   Identification of IL-2Rα as a sushi-domain-dependent binding partner of SUSD2 that blocks IL-2 signaling provided a direct molecular mechanism for SUSD2-mediated CD8+ T cell suppression and explained why Susd2-knockout CAR-T cells exhibit enhanced antitumor activity.

   Evidence Quantitative MS interactome, Susd2−/− mouse genetic models, adoptive CAR-T cell transfer in multiple tumor models

   PMID:36266363

   Open questions at the time

   • Crystal structure of SUSD2–IL-2Rα complex not available
   • Contribution of SUSD2 to CD4+ T cell or Treg function not addressed
10. 2022 Medium

    Demonstration that CBX8 and SET co-occupy the SUSD2 promoter to deposit H2AK119ub and block H3 acetylation identified a specific epigenetic silencing mechanism for SUSD2 transcription in ovarian cancer.

    Evidence FLAG-AP/MS for CBX8-SET complex, ChIP for histone marks at SUSD2 promoter, knockdown/rescue

    PMID:35894945

    Open questions at the time

    • Whether CBX8-mediated repression operates in non-ovarian tissues is unknown
    • Upstream signals controlling CBX8 recruitment to SUSD2 locus not identified
11. 2023 Medium

    Conservation of function was established by showing the C. elegans ortholog DEC-7 localizes to intestinal cell junctions and clusters innexin gap junctions, linking SUSD2 family members to intercellular communication across phyla.

    Evidence Genetic epistasis with inx-16 mutants, immunofluorescence in C. elegans intestinal epithelium, behavioral assays

    PMID:37067458

    Open questions at the time

    • Whether mammalian SUSD2 similarly organizes gap junctions not tested
    • Direct physical interaction between DEC-7 and INX-16 not demonstrated
12. 2025 Medium

    Identification of CSBF as a cytokine ligand for SUSD2 on keratinocytes established SUSD2 as a bona fide cytokine receptor that dampens psoriatic inflammation by sequestering ACT1 away from TRAF6/TNFR1.

    Evidence Co-IP competition assays, SUSD2 KO, Csbf−/− IMQ-induced psoriasis mouse model, cytokine signaling analysis

    PMID:40804449

    Open questions at the time

    • CSBF–SUSD2 binding affinity and stoichiometry not quantified
    • Relevance to human psoriasis not directly demonstrated
13. 2025 Medium

    Site-specific sialylation of SUSD2 at Asn162 by ST3GAL4 in cancer-associated fibroblasts was shown to enhance AKT/Smad2 binding and phosphorylation, establishing that post-translational glycosylation tunes SUSD2's signaling output in the tumor stroma.

    Evidence Intact glycopeptide MS, Co-IP of sialylated SUSD2 with AKT and Smad2, phosphorylation blots in lung adenocarcinoma CAFs

    PMID:40846295

    Open questions at the time

    • Whether sialylation affects SUSD2 interactions with IL-2Rα or galectin-1 is untested
    • In vivo relevance of glycosylation-dependent signaling not demonstrated
14. 2026 Medium

    Demonstration that SUSD2 binds integrin β1 and activates FAK/focal adhesion signaling—including adhesion-independent FAK activation in spheroids—resolved the long-standing question of which adhesion receptor mediates SUSD2-driven motility.

    Evidence Co-IP of SUSD2–integrin β1, FAK phosphorylation blots, focal adhesion imaging, orthotopic pancreatic cancer transplantation

    PMID:41513453

    Open questions at the time

    • Whether integrin β1 interaction requires GDPH cleavage unknown
    • Adhesion-independent FAK activation mechanism not elucidated

• The identity of the serine protease that cleaves SUSD2 at the GDPH site remains unknown, and no structural information exists for SUSD2 or any of its receptor complexes (IL-2Rα, integrin β1, CSBF); additionally, how context determines whether SUSD2 promotes or suppresses tumor progression across cancer types is unresolved.
• Cleaving protease identity unknown
• No crystal or cryo-EM structure of SUSD2 or its complexes
• Context-dependent pro- vs anti-tumorigenic signaling logic not resolved