{"gene":"SUSD2","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":2007,"finding":"SUSD2 (mouse Susd2/SVS-1) is a type I transmembrane protein localized to the plasma membrane with its N-terminus on the extracellular surface; it contains functional domains inherent to adhesion molecules including a von Willebrand factor type D (vWD) domain, and its expression inhibits clonogenicity, anchorage-independent growth, migration, and invasion of cancer cells in vitro.","method":"Confocal microscopy with N- and C-terminal FLAG/peptide antibodies, adenoviral transduction, Matrigel invasion assay, anchorage-independent growth assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiments with functional consequence, multiple phenotypic assays in single lab","pmids":["17428258"],"is_preprint":false},{"year":2007,"finding":"Mutation of conserved GLLG residues (positions 591–594) in the vWD domain of SUSD2 (SVS-1-vWD(m)) inverts membrane topology so both N- and C-termini localize intracellularly; this mutant induces apoptosis via caspase-3/9 activation (mitochondrial pathway) and Akt dephosphorylation, whereas wild-type SUSD2 does not induce apoptosis.","method":"Confocal microscopy with tagged constructs, adenoviral transduction, caspase activity assays, Akt phosphorylation western blot, nuclear/DNA fragmentation assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 1–2 — mutagenesis with mechanistic follow-up (caspase activation, Akt signaling) in single lab","pmids":["17428257"],"is_preprint":false},{"year":2012,"finding":"SUSD2 interacts with galectin-1 (Gal-1) and is required for Gal-1 surface presentation on breast cancer cells; loss of SUSD2 prevents Gal-1 localization to the cell surface, and SUSD2 expression promotes Jurkat T cell apoptosis in co-culture.","method":"Co-immunoprecipitation, cell surface staining/flow cytometry, T cell apoptosis co-culture assay","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP binding partner identified with functional consequence (T cell apoptosis), single lab","pmids":["23131994"],"is_preprint":false},{"year":2015,"finding":"In rat hippocampal neurons, Susd2 localizes to soma, axons, and dendrites and preferentially associates with excitatory synapses; shRNA-mediated knockdown selectively reduces excitatory synaptic profiles, increases dendritic tree length, and decreases axon elongation.","method":"shRNA knockdown, immunofluorescence/confocal imaging, synapse counting, morphometric analysis of neurites","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional consequence (synapse number, neurite morphology), single lab","pmids":["25724483"],"is_preprint":false},{"year":2019,"finding":"SUSD2 is proteolytically cleaved at its GDPH amino acid sequence by a serine protease; cleavage is required for SUSD2 and Gal-1 plasma membrane localization, as a noncleavable GDPH-deletion mutant and cysteine (disulfide bond) mutants fail to present Gal-1 at the cell surface.","method":"Site-directed mutagenesis, western immunoblot, serine protease inhibitor (Pefabloc SC) treatment, cell surface flow cytometry","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of cleavage site + pharmacological inhibition + cell surface assay, multiple orthogonal approaches in one study","pmids":["31387209"],"is_preprint":false},{"year":2017,"finding":"SUSD2 expression on breast cancer cells increases secretion of MCP-1/CCL2, promoting recruitment of macrophages into the tumor microenvironment and their polarization toward the M2 pro-angiogenic phenotype.","method":"SUSD2 knockdown/overexpression, qRT-PCR, western blot, ELISA for secreted MCP-1, in vitro co-culture macrophage polarization assay, in vivo syngeneic mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (molecular + cellular + in vivo), single lab","pmids":["28475599"],"is_preprint":false},{"year":2017,"finding":"TGFβ treatment of endometrial cancer cells (Ishikawa) reduces SUSD2 expression via SMAD2/3 signaling; siRNA silencing of SUSD2 activates SMAD2/3 and causes cellular senescence and cell death.","method":"siRNA knockdown, TGFβ treatment, FACS, western blot for SMAD2/3, β-galactosidase senescence staining, propidium iodide cell death assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement via loss-of-function with defined molecular readout (SMAD2/3 activation), single lab","pmids":["28841682"],"is_preprint":false},{"year":2018,"finding":"SUSD2 promotes epithelial-mesenchymal transition (EMT) in ovarian cancer downstream of Notch3 signaling, and does so through regulating EpCAM expression; EpCAM silencing reverses SUSD2-induced E-cadherin reduction and cell migration.","method":"SUSD2 overexpression/knockdown, EpCAM siRNA rescue, migration assays, western blot for EMT markers, in vivo xenograft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis rescue experiment (EpCAM silencing reversal) placing SUSD2 in Notch3-EpCAM-EMT pathway, single lab","pmids":["29305171"],"is_preprint":false},{"year":2022,"finding":"SUSD2 interacts with IL-2 receptor α (IL-2Rα/CD25) through its sushi domain and suppresses IL-2 binding to IL-2Rα, thereby impairing CD8+ T cell effector function; Susd2-/- CD8+ T cells show enhanced antitumor molecule production and Susd2-/- CAR-T cells show robust antitumor responses in mouse models.","method":"Quantitative mass spectrometry interactome, Susd2-/- mouse models, adoptive CAR-T transfer, cytokine/effector molecule quantification","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative MS identified IL-2Rα interaction, sushi-domain dependence established, validated in Susd2-/- genetic models with multiple tumor models","pmids":["36266363"],"is_preprint":false},{"year":2022,"finding":"CBX8, together with SET (an INHAT subunit), co-binds the SUSD2 promoter to establish H2AK119 ubiquitination and prevent H3 acetylation, resulting in transcriptional repression of SUSD2 in ovarian cancer cells.","method":"FLAG affinity purification coupled with mass spectrometry, ChIP, RNA-seq, CBX8/SET knockdown/overexpression, functional rescue experiments","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 — MS-identified complex + ChIP demonstrating promoter co-occupancy + histone mark analysis, single lab","pmids":["35894945"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, DEC-7/SUSD2 localizes to cell-cell junctions of intestinal epithelial cells and is required for clustering of the innexin gap junction protein INX-16 at these junctions; loss of dec-7 increases InsP3 receptor-dependent rhythmic posterior body wall muscle contractions in an INX-16-dependent manner.","method":"Genetic mutant analysis, immunofluorescence localization, epistasis with inx-16 mutants, behavioral assays","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis + direct localization of gap junction protein clustering, C. elegans ortholog model","pmids":["37067458"],"is_preprint":false},{"year":2024,"finding":"SUSD2 expression in HER2+ breast cancer cells is driven downstream of STAT3 signaling; STAT3-specific inhibitor C188-9 decreases SUSD2 expression, placing SUSD2 downstream of STAT3 in the HER2-EGFR signaling axis.","method":"Kinase array, STAT3 inhibitor (C188-9) treatment, western blot, correlation analysis with HER2/EGFR expression","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 — pharmacological inhibition with western blot only, single lab, no direct transcription factor binding shown","pmids":["39791720"],"is_preprint":false},{"year":2025,"finding":"CSBF cytokine signals through SUSD2 as its receptor on keratinocytes; the CSBF-SUSD2 complex competes with TRAF6 and TNFR1 for binding to ACT1, thereby inhibiting both IL-17A and TNF-α signaling pathways and suppressing psoriatic inflammation.","method":"Co-immunoprecipitation/competition assays, SUSD2 knockout/knockdown, Csbf-/- mouse model (IMQ-induced psoriasis), cytokine signaling pathway analysis","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-ligand interaction identified with mechanistic competition assay and in vivo genetic model, single lab","pmids":["40804449"],"is_preprint":false},{"year":2025,"finding":"ST3GAL4-mediated sialylation of SUSD2 at Asn162 in cancer-associated fibroblasts enhances binding to AKT and Smad2, increasing their phosphorylation and ECM secretion, thereby promoting pro-tumorigenic CAF activity in early lung adenocarcinoma.","method":"Mass spectrometry-based glycoproteomics, intact glycopeptide quantification, co-immunoprecipitation of sialylated SUSD2 with AKT/Smad2, phosphorylation western blot","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — site-specific glycopeptide MS + Co-IP with functional phosphorylation readout, single lab","pmids":["40846295"],"is_preprint":false},{"year":2026,"finding":"SUSD2 binds integrin β1 and promotes FAK phosphorylation and focal adhesion complex formation in pancreatic cancer cells adhering to collagen I or fibronectin, driving cell motility; in spheroid (non-adherent) cultures, SUSD2 elevates FAK phosphorylation independently of cell adhesion to promote proliferation.","method":"Co-immunoprecipitation of SUSD2 with integrin β1, FAK phosphorylation western blot, focal adhesion imaging, SUSD2 overexpression in vitro motility assays, orthotopic mouse transplantation","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP binding partner + downstream phosphorylation assay + in vivo model, single lab","pmids":["41513453"],"is_preprint":false}],"current_model":"SUSD2 is a type I transmembrane protein cleaved at a GDPH sequence by a serine protease (requiring inter-fragment disulfide bonds) to achieve plasma membrane localization, where it functions as an adhesion/signaling molecule: it presents galectin-1 on the cancer cell surface to promote immune evasion, interacts with IL-2Rα via its sushi domain to suppress CD8+ T cell effector function, binds integrin β1 to activate FAK-mediated motility, acts as a receptor for the cytokine CSBF to inhibit IL-17A/TNF-α inflammatory signaling via ACT1 competition, and in neurons localizes to excitatory synapses to regulate synapse number and neurite growth."},"narrative":{"teleology":[{"year":2007,"claim":"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","pmids":["17428258"],"confidence":"Medium","gaps":["No endogenous binding partners identified","Tumor-suppressive phenotype shown only in vitro","Adhesion ligand not determined"]},{"year":2007,"claim":"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","pmids":["17428257"],"confidence":"Medium","gaps":["Mechanism of topology sensing unknown","Relevance of GLLG mutant to physiological processing unclear"]},{"year":2012,"claim":"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","pmids":["23131994"],"confidence":"Medium","gaps":["Binding interface between SUSD2 and Gal-1 not mapped","In vivo immune evasion not demonstrated at this stage"]},{"year":2015,"claim":"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","pmids":["25724483"],"confidence":"Medium","gaps":["Synaptic binding partner not identified","Mechanism of selective excitatory synapse association unknown","No in vivo knockout behavioral phenotype reported"]},{"year":2017,"claim":"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","pmids":["28475599"],"confidence":"Medium","gaps":["Signaling pathway from SUSD2 to MCP-1 transcription not defined","Macrophage polarization not confirmed in patient tumors"]},{"year":2017,"claim":"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","pmids":["28841682"],"confidence":"Medium","gaps":["Whether SUSD2 directly modulates SMAD2/3 or acts indirectly is unclear","Senescence phenotype not validated in vivo"]},{"year":2018,"claim":"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","pmids":["29305171"],"confidence":"Medium","gaps":["Direct physical interaction between SUSD2 and EpCAM not tested","Mechanism by which SUSD2 regulates EpCAM expression unknown"]},{"year":2019,"claim":"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","pmids":["31387209"],"confidence":"High","gaps":["Identity of the cleaving serine protease not determined","Structural basis of fragment reassociation not resolved"]},{"year":2022,"claim":"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","pmids":["36266363"],"confidence":"High","gaps":["Crystal structure of SUSD2–IL-2Rα complex not available","Contribution of SUSD2 to CD4+ T cell or Treg function not addressed"]},{"year":2022,"claim":"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","pmids":["35894945"],"confidence":"Medium","gaps":["Whether CBX8-mediated repression operates in non-ovarian tissues is unknown","Upstream signals controlling CBX8 recruitment to SUSD2 locus not identified"]},{"year":2023,"claim":"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","pmids":["37067458"],"confidence":"Medium","gaps":["Whether mammalian SUSD2 similarly organizes gap junctions not tested","Direct physical interaction between DEC-7 and INX-16 not demonstrated"]},{"year":2025,"claim":"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","pmids":["40804449"],"confidence":"Medium","gaps":["CSBF–SUSD2 binding affinity and stoichiometry not quantified","Relevance to human psoriasis not directly demonstrated"]},{"year":2025,"claim":"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","pmids":["40846295"],"confidence":"Medium","gaps":["Whether sialylation affects SUSD2 interactions with IL-2Rα or galectin-1 is untested","In vivo relevance of glycosylation-dependent signaling not demonstrated"]},{"year":2026,"claim":"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","pmids":["41513453"],"confidence":"Medium","gaps":["Whether integrin β1 interaction requires GDPH cleavage unknown","Adhesion-independent FAK activation mechanism not elucidated"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,8,12]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,2,14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,8,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,8,13,14]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[10,14]}],"complexes":[],"partners":["LGALS1","IL2RA","ITGB1","CSBF","ACT1","AKT1","SMAD2","INX-16"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q9UGT4","full_name":"Sushi domain-containing protein 2","aliases":[],"length_aa":822,"mass_kda":90.2,"function":"May be a cytokine receptor for GPR15LG. May be a tumor suppressor; together with GPR15LG has a growth inhibitory effect on colon cancer cells which includes G1 cell cycle arrest (PubMed:25351403). May play a role in breast tumorigenesis (PubMed:23131994)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UGT4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SUSD2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SUSD2","total_profiled":1310},"omim":[{"mim_id":"617775","title":"G PROTEIN-COUPLED RECEPTOR 15 LIGAND; GPR15LG","url":"https://www.omim.org/entry/617775"},{"mim_id":"615825","title":"SUSHI DOMAIN-CONTAINING PROTEIN 2; SUSD2","url":"https://www.omim.org/entry/615825"},{"mim_id":"150570","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 1; LGALS1","url":"https://www.omim.org/entry/150570"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":59.3},{"tissue":"lung","ntpm":94.2}],"url":"https://www.proteinatlas.org/search/SUSD2"},"hgnc":{"alias_symbol":["BK65A6.2","FLJ22778","W5C5"],"prev_symbol":[]},"alphafold":{"accession":"Q9UGT4","domains":[{"cath_id":"2.60.40.10","chopping":"63-147","consensus_level":"high","plddt":92.3176,"start":63,"end":147},{"cath_id":"-","chopping":"284-431","consensus_level":"high","plddt":95.0497,"start":284,"end":431},{"cath_id":"3.40.1000.10","chopping":"444-640","consensus_level":"high","plddt":93.1279,"start":444,"end":640},{"cath_id":"2.10.70.10","chopping":"733-779","consensus_level":"high","plddt":96.8064,"start":733,"end":779},{"cath_id":"2.60.40","chopping":"157-281","consensus_level":"high","plddt":95.7778,"start":157,"end":281}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGT4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGT4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGT4-F1-predicted_aligned_error_v6.png","plddt_mean":90.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUSD2","jax_strain_url":"https://www.jax.org/strain/search?query=SUSD2"},"sequence":{"accession":"Q9UGT4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UGT4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UGT4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGT4"}},"corpus_meta":[{"pmid":"23131994","id":"PMC_23131994","title":"Multiple functions of sushi domain containing 2 (SUSD2) in breast tumorigenesis.","date":"2012","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/23131994","citation_count":73,"is_preprint":false},{"pmid":"17428258","id":"PMC_17428258","title":"Isolation of a novel mouse gene, mSVS-1/SUSD2, reversing tumorigenic phenotypes of cancer cells in vitro.","date":"2007","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/17428258","citation_count":38,"is_preprint":false},{"pmid":"29305171","id":"PMC_29305171","title":"SUSD2 promotes cancer metastasis and confers cisplatin resistance in high grade serous ovarian cancer.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29305171","citation_count":36,"is_preprint":false},{"pmid":"26815503","id":"PMC_26815503","title":"SUSD2 is frequently downregulated and functions as a tumor suppressor in RCC and lung cancer.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26815503","citation_count":31,"is_preprint":false},{"pmid":"28475599","id":"PMC_28475599","title":"SUSD2 promotes tumor-associated macrophage recruitment by increasing levels of MCP-1 in breast cancer.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28475599","citation_count":31,"is_preprint":false},{"pmid":"27775699","id":"PMC_27775699","title":"SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance.","date":"2016","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27775699","citation_count":26,"is_preprint":false},{"pmid":"36266363","id":"PMC_36266363","title":"SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling.","date":"2022","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36266363","citation_count":22,"is_preprint":false},{"pmid":"28841682","id":"PMC_28841682","title":"Downregulation of endometrial mesenchymal marker SUSD2 causes cell senescence and cell death in endometrial carcinoma cells.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28841682","citation_count":22,"is_preprint":false},{"pmid":"25724483","id":"PMC_25724483","title":"The Susd2 protein regulates neurite growth and excitatory synaptic density in hippocampal cultures.","date":"2015","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/25724483","citation_count":17,"is_preprint":false},{"pmid":"31387209","id":"PMC_31387209","title":"SUSD2 Proteolytic Cleavage Requires the GDPH Sequence and Inter-Fragment Disulfide Bonds for Surface Presentation of Galectin-1 on Breast Cancer Cells.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31387209","citation_count":17,"is_preprint":false},{"pmid":"26741828","id":"PMC_26741828","title":"Isolation and Localization of Mesenchymal Stem Cells in Human Palatine Tonsil by W5C5 (SUSD2).","date":"2016","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26741828","citation_count":15,"is_preprint":false},{"pmid":"32432739","id":"PMC_32432739","title":"TPM4 aggravates the malignant progression of hepatocellular carcinoma through negatively regulating SUSD2.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32432739","citation_count":15,"is_preprint":false},{"pmid":"34575617","id":"PMC_34575617","title":"Endometrial SUSD2+ Mesenchymal Stem/Stromal Cells in Tissue Engineering: Advances in Novel Cellular Constructs for Pelvic Organ Prolapse.","date":"2021","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34575617","citation_count":15,"is_preprint":false},{"pmid":"17428257","id":"PMC_17428257","title":"von Willebrand factor type D domain mutant of SVS-1/SUSD2, vWD(m), induces apoptosis in HeLa cells.","date":"2007","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/17428257","citation_count":13,"is_preprint":false},{"pmid":"33961124","id":"PMC_33961124","title":"Identification and characterisation of maternal perivascular SUSD2+ placental mesenchymal stem/stromal cells.","date":"2021","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/33961124","citation_count":12,"is_preprint":false},{"pmid":"35093718","id":"PMC_35093718","title":"The fate of human SUSD2+ endometrial mesenchymal stem cells during decidualization.","date":"2022","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35093718","citation_count":10,"is_preprint":false},{"pmid":"35894945","id":"PMC_35894945","title":"CBX8 Together with SET Facilitates Ovarian Carcinoma Growth and Metastasis by Suppressing the Transcription of SUSD2.","date":"2022","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/35894945","citation_count":10,"is_preprint":false},{"pmid":"38897441","id":"PMC_38897441","title":"The dual role of SUSD2 in cancer development.","date":"2024","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38897441","citation_count":8,"is_preprint":false},{"pmid":"32595828","id":"PMC_32595828","title":"SUSD2 expression correlates with decreased metastasis and increased survival in a high-grade serous ovarian cancer xenograft murine model.","date":"2020","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/32595828","citation_count":8,"is_preprint":false},{"pmid":"30335544","id":"PMC_30335544","title":"Sushi Domain Containing 2 (SUSD2) inhibits platelet activation and binding to high-grade serous ovarian carcinoma cells.","date":"2018","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/30335544","citation_count":6,"is_preprint":false},{"pmid":"34096216","id":"PMC_34096216","title":"In Vitro Implantation Model Using Human Endometrial SUSD2+ Mesenchymal Stem Cells and Myometrial Smooth Muscle Cells.","date":"2021","source":"Cell journal","url":"https://pubmed.ncbi.nlm.nih.gov/34096216","citation_count":5,"is_preprint":false},{"pmid":"37067458","id":"PMC_37067458","title":"DEC-7/SUSD2, a sushi domain-containing protein, regulates an ultradian behavior mediated by intestinal epithelial Ca2+ oscillations in Caenorhabditis elegans.","date":"2023","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37067458","citation_count":3,"is_preprint":false},{"pmid":"32620384","id":"PMC_32620384","title":"Genetic variants in SUSD2 are associated with the risk of ischemic heart disease.","date":"2020","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/32620384","citation_count":3,"is_preprint":false},{"pmid":"39791720","id":"PMC_39791720","title":"Induction of SUSD2 by STAT3 Activation Is Associated with Tumor Recurrence in HER2-Positive Breast Cancer.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39791720","citation_count":2,"is_preprint":false},{"pmid":"40804449","id":"PMC_40804449","title":"The cytokine CSBF inhibits the IL-17A and TNF-α inflammatory pathways via SUSD2-ACT1 in keratinocytes and alleviates IMQ-induced psoriasis.","date":"2025","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40804449","citation_count":1,"is_preprint":false},{"pmid":"40846295","id":"PMC_40846295","title":"SUSD2 hypersialylation promotes early lung adenocarcinoma progression by driving ECM remodeling and pro-tumorigenic fibroblast activation.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/40846295","citation_count":0,"is_preprint":false},{"pmid":"40882394","id":"PMC_40882394","title":"Dysregulation of SUSD2-CLDN18.2-mediated cell adhesion contributes to lung adenocarcinoma progression associated with chronic low-dose nanoplastics exposure.","date":"2025","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/40882394","citation_count":0,"is_preprint":false},{"pmid":"41513453","id":"PMC_41513453","title":"SUSD2 Promotes Metastasis and Primary Tumor Growth in Pancreatic Cancer Cells via Integrin-FAK Signaling Activation.","date":"2026","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/41513453","citation_count":0,"is_preprint":false},{"pmid":"41013639","id":"PMC_41013639","title":"Single-cell RNA sequencing of endometrium uncovers dynamic characteristics and dysregulation of perivascular CD9+SUSD2+ cells in thin endometrium.","date":"2025","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41013639","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.23.660982","title":"Molecular signature of human endometrial stem/progenitor cells at the single cell level","date":"2025-06-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.23.660982","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.11.24311581","title":"Integrative Multi-omics Approach Reveals the Molecular Characterization and Differences of ECM-PI3K-Akt Pathway among Coronary Artery Bypass Grafting Conduits with Clinical Implications","date":"2024-08-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.11.24311581","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18351,"output_tokens":3619,"usd":0.054669},"stage2":{"model":"claude-opus-4-6","input_tokens":7075,"output_tokens":3507,"usd":0.184575},"total_usd":0.239244,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"SUSD2 (mouse Susd2/SVS-1) is a type I transmembrane protein localized to the plasma membrane with its N-terminus on the extracellular surface; it contains functional domains inherent to adhesion molecules including a von Willebrand factor type D (vWD) domain, and its expression inhibits clonogenicity, anchorage-independent growth, migration, and invasion of cancer cells in vitro.\",\n      \"method\": \"Confocal microscopy with N- and C-terminal FLAG/peptide antibodies, adenoviral transduction, Matrigel invasion assay, anchorage-independent growth assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional consequence, multiple phenotypic assays in single lab\",\n      \"pmids\": [\"17428258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mutation of conserved GLLG residues (positions 591–594) in the vWD domain of SUSD2 (SVS-1-vWD(m)) inverts membrane topology so both N- and C-termini localize intracellularly; this mutant induces apoptosis via caspase-3/9 activation (mitochondrial pathway) and Akt dephosphorylation, whereas wild-type SUSD2 does not induce apoptosis.\",\n      \"method\": \"Confocal microscopy with tagged constructs, adenoviral transduction, caspase activity assays, Akt phosphorylation western blot, nuclear/DNA fragmentation assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis with mechanistic follow-up (caspase activation, Akt signaling) in single lab\",\n      \"pmids\": [\"17428257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUSD2 interacts with galectin-1 (Gal-1) and is required for Gal-1 surface presentation on breast cancer cells; loss of SUSD2 prevents Gal-1 localization to the cell surface, and SUSD2 expression promotes Jurkat T cell apoptosis in co-culture.\",\n      \"method\": \"Co-immunoprecipitation, cell surface staining/flow cytometry, T cell apoptosis co-culture assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP binding partner identified with functional consequence (T cell apoptosis), single lab\",\n      \"pmids\": [\"23131994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In rat hippocampal neurons, Susd2 localizes to soma, axons, and dendrites and preferentially associates with excitatory synapses; shRNA-mediated knockdown selectively reduces excitatory synaptic profiles, increases dendritic tree length, and decreases axon elongation.\",\n      \"method\": \"shRNA knockdown, immunofluorescence/confocal imaging, synapse counting, morphometric analysis of neurites\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence (synapse number, neurite morphology), single lab\",\n      \"pmids\": [\"25724483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SUSD2 is proteolytically cleaved at its GDPH amino acid sequence by a serine protease; cleavage is required for SUSD2 and Gal-1 plasma membrane localization, as a noncleavable GDPH-deletion mutant and cysteine (disulfide bond) mutants fail to present Gal-1 at the cell surface.\",\n      \"method\": \"Site-directed mutagenesis, western immunoblot, serine protease inhibitor (Pefabloc SC) treatment, cell surface flow cytometry\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of cleavage site + pharmacological inhibition + cell surface assay, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"31387209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SUSD2 expression on breast cancer cells increases secretion of MCP-1/CCL2, promoting recruitment of macrophages into the tumor microenvironment and their polarization toward the M2 pro-angiogenic phenotype.\",\n      \"method\": \"SUSD2 knockdown/overexpression, qRT-PCR, western blot, ELISA for secreted MCP-1, in vitro co-culture macrophage polarization assay, in vivo syngeneic mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (molecular + cellular + in vivo), single lab\",\n      \"pmids\": [\"28475599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGFβ treatment of endometrial cancer cells (Ishikawa) reduces SUSD2 expression via SMAD2/3 signaling; siRNA silencing of SUSD2 activates SMAD2/3 and causes cellular senescence and cell death.\",\n      \"method\": \"siRNA knockdown, TGFβ treatment, FACS, western blot for SMAD2/3, β-galactosidase senescence staining, propidium iodide cell death assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement via loss-of-function with defined molecular readout (SMAD2/3 activation), single lab\",\n      \"pmids\": [\"28841682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SUSD2 promotes epithelial-mesenchymal transition (EMT) in ovarian cancer downstream of Notch3 signaling, and does so through regulating EpCAM expression; EpCAM silencing reverses SUSD2-induced E-cadherin reduction and cell migration.\",\n      \"method\": \"SUSD2 overexpression/knockdown, EpCAM siRNA rescue, migration assays, western blot for EMT markers, in vivo xenograft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis rescue experiment (EpCAM silencing reversal) placing SUSD2 in Notch3-EpCAM-EMT pathway, single lab\",\n      \"pmids\": [\"29305171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SUSD2 interacts with IL-2 receptor α (IL-2Rα/CD25) through its sushi domain and suppresses IL-2 binding to IL-2Rα, thereby impairing CD8+ T cell effector function; Susd2-/- CD8+ T cells show enhanced antitumor molecule production and Susd2-/- CAR-T cells show robust antitumor responses in mouse models.\",\n      \"method\": \"Quantitative mass spectrometry interactome, Susd2-/- mouse models, adoptive CAR-T transfer, cytokine/effector molecule quantification\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative MS identified IL-2Rα interaction, sushi-domain dependence established, validated in Susd2-/- genetic models with multiple tumor models\",\n      \"pmids\": [\"36266363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CBX8, together with SET (an INHAT subunit), co-binds the SUSD2 promoter to establish H2AK119 ubiquitination and prevent H3 acetylation, resulting in transcriptional repression of SUSD2 in ovarian cancer cells.\",\n      \"method\": \"FLAG affinity purification coupled with mass spectrometry, ChIP, RNA-seq, CBX8/SET knockdown/overexpression, functional rescue experiments\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified complex + ChIP demonstrating promoter co-occupancy + histone mark analysis, single lab\",\n      \"pmids\": [\"35894945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, DEC-7/SUSD2 localizes to cell-cell junctions of intestinal epithelial cells and is required for clustering of the innexin gap junction protein INX-16 at these junctions; loss of dec-7 increases InsP3 receptor-dependent rhythmic posterior body wall muscle contractions in an INX-16-dependent manner.\",\n      \"method\": \"Genetic mutant analysis, immunofluorescence localization, epistasis with inx-16 mutants, behavioral assays\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis + direct localization of gap junction protein clustering, C. elegans ortholog model\",\n      \"pmids\": [\"37067458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SUSD2 expression in HER2+ breast cancer cells is driven downstream of STAT3 signaling; STAT3-specific inhibitor C188-9 decreases SUSD2 expression, placing SUSD2 downstream of STAT3 in the HER2-EGFR signaling axis.\",\n      \"method\": \"Kinase array, STAT3 inhibitor (C188-9) treatment, western blot, correlation analysis with HER2/EGFR expression\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibition with western blot only, single lab, no direct transcription factor binding shown\",\n      \"pmids\": [\"39791720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CSBF cytokine signals through SUSD2 as its receptor on keratinocytes; the CSBF-SUSD2 complex competes with TRAF6 and TNFR1 for binding to ACT1, thereby inhibiting both IL-17A and TNF-α signaling pathways and suppressing psoriatic inflammation.\",\n      \"method\": \"Co-immunoprecipitation/competition assays, SUSD2 knockout/knockdown, Csbf-/- mouse model (IMQ-induced psoriasis), cytokine signaling pathway analysis\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-ligand interaction identified with mechanistic competition assay and in vivo genetic model, single lab\",\n      \"pmids\": [\"40804449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST3GAL4-mediated sialylation of SUSD2 at Asn162 in cancer-associated fibroblasts enhances binding to AKT and Smad2, increasing their phosphorylation and ECM secretion, thereby promoting pro-tumorigenic CAF activity in early lung adenocarcinoma.\",\n      \"method\": \"Mass spectrometry-based glycoproteomics, intact glycopeptide quantification, co-immunoprecipitation of sialylated SUSD2 with AKT/Smad2, phosphorylation western blot\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific glycopeptide MS + Co-IP with functional phosphorylation readout, single lab\",\n      \"pmids\": [\"40846295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SUSD2 binds integrin β1 and promotes FAK phosphorylation and focal adhesion complex formation in pancreatic cancer cells adhering to collagen I or fibronectin, driving cell motility; in spheroid (non-adherent) cultures, SUSD2 elevates FAK phosphorylation independently of cell adhesion to promote proliferation.\",\n      \"method\": \"Co-immunoprecipitation of SUSD2 with integrin β1, FAK phosphorylation western blot, focal adhesion imaging, SUSD2 overexpression in vitro motility assays, orthotopic mouse transplantation\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP binding partner + downstream phosphorylation assay + in vivo model, single lab\",\n      \"pmids\": [\"41513453\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUSD2 is a type I transmembrane protein cleaved at a GDPH sequence by a serine protease (requiring inter-fragment disulfide bonds) to achieve plasma membrane localization, where it functions as an adhesion/signaling molecule: it presents galectin-1 on the cancer cell surface to promote immune evasion, interacts with IL-2Rα via its sushi domain to suppress CD8+ T cell effector function, binds integrin β1 to activate FAK-mediated motility, acts as a receptor for the cytokine CSBF to inhibit IL-17A/TNF-α inflammatory signaling via ACT1 competition, and in neurons localizes to excitatory synapses to regulate synapse number and neurite growth.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing SUSD2 as a surface-oriented adhesion-class transmembrane protein with tumor-suppressive properties answered the foundational question of its topology and cellular role.\",\n      \"evidence\": \"Confocal microscopy of tagged SUSD2 plus functional assays (clonogenicity, migration, invasion) in cancer cell lines\",\n      \"pmids\": [\"17428258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous binding partners identified\", \"Tumor-suppressive phenotype shown only in vitro\", \"Adhesion ligand not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Site-directed mutagenesis of GLLG591–594 with caspase-3/9 activity assays and Akt phosphorylation blots\",\n      \"pmids\": [\"17428257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of topology sensing unknown\", \"Relevance of GLLG mutant to physiological processing unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation of SUSD2–Gal-1, surface flow cytometry, Jurkat T cell co-culture apoptosis assay\",\n      \"pmids\": [\"23131994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface between SUSD2 and Gal-1 not mapped\", \"In vivo immune evasion not demonstrated at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that Susd2 localizes to excitatory synapses and regulates synapse number and neurite morphology expanded its functional scope beyond cancer to neuronal development.\",\n      \"evidence\": \"shRNA knockdown in rat hippocampal neurons with confocal synapse counting and morphometric analysis\",\n      \"pmids\": [\"25724483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synaptic binding partner not identified\", \"Mechanism of selective excitatory synapse association unknown\", \"No in vivo knockout behavioral phenotype reported\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"SUSD2 knockdown/overexpression with ELISA, macrophage co-culture, syngeneic mouse tumor model\",\n      \"pmids\": [\"28475599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway from SUSD2 to MCP-1 transcription not defined\", \"Macrophage polarization not confirmed in patient tumors\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"TGFβ treatment, siRNA silencing, SMAD2/3 phosphorylation blots, β-galactosidase senescence staining in endometrial cancer cells\",\n      \"pmids\": [\"28841682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SUSD2 directly modulates SMAD2/3 or acts indirectly is unclear\", \"Senescence phenotype not validated in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Epistasis experiments positioned SUSD2 downstream of Notch3 and upstream of EpCAM in an EMT signaling cascade in ovarian cancer, providing a defined signaling hierarchy.\",\n      \"evidence\": \"SUSD2 overexpression/knockdown with EpCAM siRNA rescue, EMT marker blots, xenograft\",\n      \"pmids\": [\"29305171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between SUSD2 and EpCAM not tested\", \"Mechanism by which SUSD2 regulates EpCAM expression unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"GDPH-deletion and cysteine mutagenesis, Pefabloc SC protease inhibition, cell surface flow cytometry\",\n      \"pmids\": [\"31387209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cleaving serine protease not determined\", \"Structural basis of fragment reassociation not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Quantitative MS interactome, Susd2−/− mouse genetic models, adoptive CAR-T cell transfer in multiple tumor models\",\n      \"pmids\": [\"36266363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of SUSD2–IL-2Rα complex not available\", \"Contribution of SUSD2 to CD4+ T cell or Treg function not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"FLAG-AP/MS for CBX8-SET complex, ChIP for histone marks at SUSD2 promoter, knockdown/rescue\",\n      \"pmids\": [\"35894945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CBX8-mediated repression operates in non-ovarian tissues is unknown\", \"Upstream signals controlling CBX8 recruitment to SUSD2 locus not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic epistasis with inx-16 mutants, immunofluorescence in C. elegans intestinal epithelium, behavioral assays\",\n      \"pmids\": [\"37067458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mammalian SUSD2 similarly organizes gap junctions not tested\", \"Direct physical interaction between DEC-7 and INX-16 not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP competition assays, SUSD2 KO, Csbf−/− IMQ-induced psoriasis mouse model, cytokine signaling analysis\",\n      \"pmids\": [\"40804449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CSBF–SUSD2 binding affinity and stoichiometry not quantified\", \"Relevance to human psoriasis not directly demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Intact glycopeptide MS, Co-IP of sialylated SUSD2 with AKT and Smad2, phosphorylation blots in lung adenocarcinoma CAFs\",\n      \"pmids\": [\"40846295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether sialylation affects SUSD2 interactions with IL-2Rα or galectin-1 is untested\", \"In vivo relevance of glycosylation-dependent signaling not demonstrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of SUSD2–integrin β1, FAK phosphorylation blots, focal adhesion imaging, orthotopic pancreatic cancer transplantation\",\n      \"pmids\": [\"41513453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether integrin β1 interaction requires GDPH cleavage unknown\", \"Adhesion-independent FAK activation mechanism not elucidated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 8, 12]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 2, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 8, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 8, 13, 14]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [10, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LGALS1\",\n      \"IL2RA\",\n      \"ITGB1\",\n      \"CSBF\",\n      \"ACT1\",\n      \"AKT1\",\n      \"SMAD2\",\n      \"INX-16\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}