{"gene":"SEMA4D","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2000,"finding":"CD72 was identified as the lymphocyte receptor for CD100/SEMA4D. CD100 stimulation induced tyrosine dephosphorylation of CD72 and dissociation of the phosphatase SHP-1 from CD72, thereby switching off CD72's negative signaling in B cells.","method":"Expression cloning, binding affinity measurements (Kd), co-immunoprecipitation, tyrosine dephosphorylation assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — receptor identified by expression cloning, binding affinities measured, downstream signaling (SHP-1 dissociation) confirmed biochemically, replicated across human and mouse systems","pmids":["11114375","12882840"],"is_preprint":false},{"year":2000,"finding":"CD100/SEMA4D differentially utilizes two distinct receptors: plexin-B1 in non-lymphoid tissues and CD72 in lymphoid tissues, as demonstrated using CD100-deficient mice.","method":"CD100-knockout mouse generation, immune functional assays, genetic epistasis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotypes, replicated finding across multiple papers","pmids":["11114376"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of SEMA4D (residues 1–657) revealed a seven-bladed beta-propeller sema domain with unexpected homology to integrins, a PSI domain forming a cysteine knot, and an Ig-like domain. The homodimer is stabilized through interactions between the top faces of the beta-propeller, which also mediates ligand (receptor) binding.","method":"X-ray crystallography (crystal structure)","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional mapping of receptor-binding surface","pmids":["12958590"],"is_preprint":false},{"year":2001,"finding":"Membrane CD100 is cleaved by a metalloprotease-dependent process to release a soluble homodimeric form. Cysteine 674 in the extracellular domain is required for dimerization, and dimerization is required for proteolytic shedding. A serine kinase inhibitor (staurosporine) enhances cleavage, suggesting the process is regulated by phosphorylation.","method":"Metalloprotease inhibitor treatment, site-directed mutagenesis (C674 mutation), cell transfection, immunoprecipitation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of specific residue plus pharmacological inhibition with orthogonal methods in one study","pmids":["11254687"],"is_preprint":false},{"year":1997,"finding":"CD100 associates with a serine kinase activity in T cells and NK cells, and CD100 itself is a preferred substrate of this kinase. The kinase activity is retained by a fusion protein containing the cytoplasmic domain of CD100.","method":"Immunoprecipitation of kinase activity, cytoplasmic domain fusion protein assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase co-immunoprecipitation and cytoplasmic domain construct used, single lab with two orthogonal methods","pmids":["9295286"],"is_preprint":false},{"year":1996,"finding":"CD100 is physically associated with CD45 (protein tyrosine phosphatase) at the T cell surface, and this association has functional consequences for both molecules including effects on homotypic T cell adhesion. The association is increased during T cell activation.","method":"Co-immunoprecipitation, CD45 enzymatic PTPase activity detection, T cell aggregation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and enzymatic assay, single lab","pmids":["8955171"],"is_preprint":false},{"year":2005,"finding":"SEMA4D promotes angiogenesis in vitro and in vivo via its high-affinity receptor Plexin-B1, which couples to and activates the Met tyrosine kinase to mediate the angiogenic effects.","method":"In vitro angiogenesis assays, in vivo assays, co-immunoprecipitation of Plexin-B1 with Met, functional rescue experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro and in vivo angiogenesis with mechanistic demonstration of Plexin-B1/Met coupling, multiple orthogonal methods","pmids":["15632204"],"is_preprint":false},{"year":2002,"finding":"Plexin-B1 and PAK compete for binding to active (GTP-bound) Rac; plexin-B1 inhibits Rac-induced PAK activation. Active Rac enhances Sema4D binding to plexin-B1 and promotes plexin-B1 surface localization, demonstrating bidirectional signaling between Rac and plexin-B1.","method":"Pulldown/binding assays, PAK kinase inhibition assay, cell surface binding assays, dominant-active Rac constructs","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal in vitro biochemical assays with functional mutagenesis in a single study","pmids":["11937491"],"is_preprint":false},{"year":2006,"finding":"Plexin-B1 functions as an R-Ras GTPase-activating protein (GAP); Sema4D activates this R-Ras GAP activity, which inactivates PI3K, dephosphorylates Akt, and activates GSK-3β, leading to phosphorylation of CRMP-2 and growth cone collapse in hippocampal neurons.","method":"R-Ras GTP-loading assay, Akt/GSK-3β phosphorylation assays, constitutively active mutant expression, GSK-3 inhibitor treatment, PI3K activation rescue","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of signaling pathway, multiple mutants and pharmacological inhibitors, mechanistic pathway fully defined","pmids":["16799460"],"is_preprint":false},{"year":2007,"finding":"Sema4D activates RhoA via plexin-B1's association with PDZ-RhoGEFs, leading to increased dendritic spine density and changes in spine shape in cultured neurons. This effect requires the C-terminal PDZ-RhoGEF-binding domain of plexin-B1 and is blocked by the ROCK inhibitor Y-27632.","method":"Exogenous Sema4D application to neurons, RhoA activation assay, ROCK inhibitor treatment, plexin-B1 C-terminal deletion mutant expression","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutagenesis and pharmacological inhibition in neuronal cultures, single lab","pmids":["17950529"],"is_preprint":false},{"year":2013,"finding":"Sema4D promotes rapid GABAergic synapse assembly in rodent hippocampus via its receptor PlexinB1. Sema4D treatment increases GABAergic synapse density within 30 minutes by recruiting synaptic proteins to both pre- and postsynaptic terminals; this effect is absent in PlxnB1-/- mice.","method":"Immunocytochemistry, live imaging of synaptic protein addition, PlxnB1-knockout mice, organotypic slice epilepsy model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse validation plus live imaging and functional electrophysiology, multiple orthogonal methods","pmids":["23699507"],"is_preprint":false},{"year":2013,"finding":"Sema4D localizes to synapses as a membrane-bound protein and signals through its extracellular domain in the postsynaptic membrane to promote GABAergic synapse formation, despite being proteolytically cleaved; the membrane-bound form (not shed) is required for this function.","method":"Immunolocalization, proteolysis assays, RNAi knockdown, domain-specific functional assays in hippocampal neurons","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization and knockdown with mechanistic dissection of membrane-bound vs. shed form, single lab","pmids":["24036351"],"is_preprint":false},{"year":2013,"finding":"SEMA4D exodomain shedding in platelets is regulated by calmodulin: the membrane-proximal cytoplasmic domain (Arg762–Lys779) contains a calmodulin-binding site; calmodulin dissociates from this site upon platelet activation, which is sufficient to trigger ADAM17-dependent cleavage and release of the bioactive 120-kDa exodomain fragment.","method":"Co-precipitation, calmodulin inhibitor (W7), membrane-permeable peptide competition, deletion mutagenesis of calmodulin-binding domain","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific domain combined with pharmacological inhibitors and peptide competition, mechanistically rigorous single study","pmids":["23564909"],"is_preprint":false},{"year":2018,"finding":"STING activation in macrophages triggers ADAM17-mediated shedding of membrane-bound SEMA4D to produce soluble proinflammatory SEMA4D, independently of the TBK1/IRF3 transcriptional pathway (SEMA4D gene expression is not upregulated). This ADAM17-dependent shedding is blocked by the ADAM17 inhibitor TMI-1 but not by the TBK1 inhibitor BX795.","method":"Macrophage secretome mass spectrometry, ADAM17 inhibitor (TMI-1) treatment, TBK1 inhibitor (BX795) treatment, western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — pharmacological dissection with two inhibitors, proteomic identification, mechanistic distinction of transcriptional vs. post-translational pathway","pmids":["29618514"],"is_preprint":false},{"year":2003,"finding":"Sema4D/CD100 is expressed by oligodendrocytes and myelin in the CNS (confirmed by western blot on myelin), is strongly inhibitory for postnatal sensory and cerebellar granule cell axons in stripe assays, and is upregulated transiently in oligodendrocytes at the periphery of spinal cord lesions.","method":"Double-labeling immunohistochemistry, western blot, stripe axon-repulsion assay, neuron-oligodendrocyte co-culture, spinal cord lesion model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IHC, WB, functional stripe assay, in vivo lesion model) in a single rigorous study","pmids":["14534257"],"is_preprint":false},{"year":2004,"finding":"Soluble CD100 from activated T lymphocytes (sCD100) collapses oligodendrocyte process extensions and triggers apoptosis of immature neural/oligodendrocyte cells, likely through plexin family receptors; this was demonstrated by blocking sCD100 with specific antibodies or adding recombinant sCD100.","method":"T lymphocyte-neural cell co-culture, blocking antibody experiments, recombinant sCD100 treatment, apoptosis assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue/blockade with antibodies plus recombinant protein, receptor identity not fully resolved","pmids":["14707103"],"is_preprint":false},{"year":2012,"finding":"Plexin-B2 on keratinocytes is the CD100 receptor mediating epidermal γδ T cell function in wound healing. CD100 ligation in γδ T cells induced cellular rounding via ERK kinase and cofilin signaling; CD100 deficiency caused defective wound healing due to disrupted γδ T cell response.","method":"In vitro blocking antibodies against plexin-B2 or CD100, CD100-/- mice, wound healing assay, ERK/cofilin signaling assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse plus in vitro signaling pathway characterization with multiple orthogonal methods","pmids":["22902232"],"is_preprint":false},{"year":2005,"finding":"Soluble CD100 inhibits migration of human monocytes via plexin-C1 (VESPR/CD232), while on immature dendritic cells (which downregulate plexin-C1 and upregulate plexin-B1 during differentiation), sCD100 acts through plexin-B1 to inhibit migration and modulate cytokine production.","method":"Migration assays with competition/blocking experiments, flow cytometry of receptor expression during monocyte-to-DC differentiation, cytokine assays","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identity established by competition assays with specific antibodies, single lab, two cell types","pmids":["15746246"],"is_preprint":false},{"year":2001,"finding":"Only the dimeric form of soluble CD100 inhibits spontaneous and chemokine-induced migration of human monocytes and B cell-lineage cells. CD100 and H-SemaIII act through the same receptor on immune cells (not neuropilin-1); one anti-CD100 mAb abolishes the inhibitory effect of both semaphorins.","method":"Cell migration assay, use of monomeric vs. dimeric soluble CD100, antibody blocking, cross-competition with H-SemaIII","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional migration assays with antibody blocking and cross-competition, receptor partially defined (not neuropilin-1), single lab","pmids":["11254688"],"is_preprint":false},{"year":2009,"finding":"Sema4D promotes iNOS expression in microglia through plexin-B1 (not CD72); during EAE, Sema4D-plexin-B1 interactions in CNS-resident cells (microglia) contribute to neuroinflammation, as adoptive transfer of MOG-specific T cells into plexin-B1-deficient mice significantly attenuated EAE.","method":"Primary microglia cultures, plexin-B1-/- and CD72-/- mice, bone marrow chimeras, adoptive T cell transfer, EAE model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockout models including chimeras and adoptive transfer, mechanistic dissection of receptor specificity (plexin-B1 vs. CD72)","pmids":["20038643"],"is_preprint":false},{"year":2014,"finding":"SEMA4D signaling disrupts endothelial tight junctions forming the BBB, inhibits migration and differentiation of oligodendrocyte precursor cells (OPCs), and induces glial activation; anti-SEMA4D antibody reverses inhibitory effects on OPC survival/differentiation in vitro and preserves BBB integrity and myelination in EAE models in vivo.","method":"In vitro OPC differentiation assay with recombinant SEMA4D and antibody reversal, multiple rodent EAE models with anti-SEMA4D antibody treatment, MRI/histology","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro mechanistic rescue plus multiple in vivo models with defined cellular readouts","pmids":["25461192"],"is_preprint":false},{"year":2009,"finding":"Sema4D deficiency in ApoE-/- mice reduces intimal neovascularization and plaque macrophage infiltration, demonstrating that Sema4D (expressed by infiltrating lymphoid cells) promotes atherosclerotic plaque angiogenesis via plexin-B1 on neovascular endothelial cells.","method":"Sema4D/ApoE double-knockout mouse model, lipid staining, immunohistochemistry for plexin-B1 and CD31/isolectin B4 (neovascularization markers), macrophage counting","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic deletion model with defined vascular phenotype, single lab","pmids":["20514420"],"is_preprint":false},{"year":2009,"finding":"Sema4D deficiency reduces platelet hyperreactivity in dyslipidemia and protects against atherosclerosis development; loss of Sema4D expression reduces platelet accumulation after arterial injury and platelet aggregation on collagen under flow.","method":"sema4D-/-/LDLR-/- double-knockout mice on high-fat diet, platelet accumulation assay in vivo and ex vivo, platelet aggregation under flow","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic deletion with defined platelet functional phenotype, single lab","pmids":["19390055"],"is_preprint":false},{"year":2005,"finding":"CD100/Sema4D regulates BCR signaling sensitivity by preventing CD72 from associating with the BCR. In the absence of CD100, SHP-1 constitutively associates with CD72, causing BCR hyporesponsiveness; with age, CD100-deficient mice accumulate marginal zone B cells and develop autoimmunity.","method":"CD100-knockout mice, BCR signaling assays, co-immunoprecipitation of CD72 with BCR complex, B cell subset analysis","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with co-IP mechanistic follow-up, single lab","pmids":["16113236"],"is_preprint":false},{"year":2019,"finding":"MMP2 and MMP9 mediate shedding of membrane-bound CD100 from T cells to generate soluble CD100; patients with chronic HBV had lower serum MMP2 correlated with lower sCD100. Therapeutic sCD100 activated DCs and liver sinusoidal endothelial cells, enhanced HBV-specific CD8 T cell responses via CD72, and accelerated HBV clearance; blockade of CD72 attenuated the intrahepatic anti-HBV CD8 T cell response.","method":"MMP2/9 inhibition in vivo, recombinant sCD100 treatment, anti-CD72 blockade, DC maturation assay, HBV clearance assay","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mechanistic experiments with defined immunological readouts, identification of MMP2/9 as sheddases, single lab","pmids":["31173811"],"is_preprint":false},{"year":2020,"finding":"Sema4D/PlexinB1 signaling induces endothelial cell dysfunction in diabetic retinopathy via mDIA1, mediated through Src-dependent VE-cadherin dysfunction. Genetic disruption of Sema4D/PlexinB1 or anti-Sema4D antibody reduced pericyte loss and vascular leakage in a streptozotocin model.","method":"Genetic Sema4D/PlexinB1 disruption, intravitreal anti-Sema4D injection, endothelial cell dysfunction assays, Src-VE-cadherin phosphorylation assays, in vivo OIR/STZ models","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disruption plus antibody blockade, mechanistic pathway (mDIA1-Src-VE-cadherin) defined with multiple in vitro and in vivo methods","pmids":["31943789"],"is_preprint":false},{"year":2017,"finding":"CD100-PlexinB2 signaling in keratinocytes promotes psoriatic inflammation by activating RhoA and Rac1 GTPases, which stimulate NF-κB signaling and activate the NLRP3 inflammasome, leading to production of CXCL-1, CCL-20, IL-1β, and IL-18.","method":"siRNA knockdown of PlxnB2, soluble CD100 stimulation, RhoA/Rac1 activation assays, NF-κB reporter assays, NLRP3 inflammasome activation assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathway assays in keratinocytes, single lab","pmids":["28927892"],"is_preprint":false},{"year":2000,"finding":"CD45 (protein tyrosine phosphatase) switches its association with CD100 depending on B cell differentiation stage; in pre-B, activated B, and pre-plasma cell stages CD45 is the main PTP associated with CD100, but at the terminal plasma cell stage, CD45 is no longer the associated PTP, indicating a switch in CD100-associated phosphatase.","method":"Cell sorting, immunoprecipitation, immunodepletion, in vitro enzymatic PTP activity assay, western blotting of B cell lines and primary sorted B cells","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity measurement plus immunodepletion, single lab with multiple cell types","pmids":["10648410"],"is_preprint":false},{"year":2013,"finding":"CD100 on γδ intraepithelial lymphocytes signals to plexin-B2 on colonocytes; CD100-/- mice show exacerbated DSS-induced colitis because γδ IEL fail to produce KGF-1 in response to epithelial damage. Administration of recombinant KGF-1 to CD100-/- mice rescues the colitis phenotype.","method":"CD100-/- mice, DSS colitis model, KGF-1 production assay, recombinant KGF-1 rescue experiment","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with defined cellular mechanism and cytokine rescue, single lab","pmids":["23695512"],"is_preprint":false},{"year":2021,"finding":"A germline heterozygous K849T missense mutation in the cytosolic domain of CD100/SEMA4D causes altered T cell function (increased proliferation and impaired IFN-γ production). Knock-in mice with the homologous mutation show the same T cell IFN-γ impairment and increased susceptibility to DDC diet-induced cholangitis; transfer of wild-type T cells attenuates cholangitis.","method":"Whole-exome sequencing, knock-in mouse generation, T cell functional assays, DDC-diet cholangitis model, wild-type T cell transfer rescue","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline mutation identified, validated in knock-in mouse model with in vivo rescue experiment, multiple orthogonal methods","pmids":["33627483"],"is_preprint":false},{"year":2022,"finding":"Sema4D on CD8+ T cells interacts with PlexinB1 on choroidal pericytes in age-related macular degeneration; this interaction leads to ROR2-mediated PlexinB1 phosphorylation and pericyte activation, disrupting vascular homeostasis and promoting choroidal neovascularization.","method":"Patient-derived samples, mouse CNV models, PlexinB1 phosphorylation assays, ROR2 functional studies, anti-Sema4D antibody treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic signaling pathway in vivo and in vitro, ROR2 phosphorylation of PlexinB1 identified, single study","pmids":["40121188"],"is_preprint":false},{"year":2007,"finding":"CD100 expressed on NK cells enhances cytotoxicity and IFN-γ secretion by binding to CD72 on target cells, increasing adhesion between NK cells and their targets rather than directly mediating killing.","method":"NK cell-target cell co-culture, CD100/CD72 blocking antibodies, adhesion assays, cytotoxicity assays, IFN-γ measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antibody blocking with multiple readouts, single lab","pmids":["17786190"],"is_preprint":false},{"year":2018,"finding":"MMP14 mediates membrane CD100 shedding in macrophages in response to PLXNB2-containing exosomes derived from OVA-challenged airway epithelial cells. Knockdown of Mmp14 in macrophages prevents CD100 cleavage and reduces pro-inflammatory chemokine transcription.","method":"Exosome isolation and aspiration, MMP14 knockdown in macrophages, CD100 shedding assay, chemokine transcription analysis","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific sheddase (MMP14) identified by knockdown with functional readout, single lab","pmids":["34414666"],"is_preprint":false},{"year":2022,"finding":"Sema4D facilitates recruitment of dental stem cells (SHED) as mural cells during angiogenesis by acting on endothelial-plexin-B1 and inducing expression of PDGF-BB, a mural cell recruitment factor, in a 3D microfluidic platform.","method":"3D biomimetic microfluidic device, pharmacological and genetic manipulation of Sema4D/plexin-B1 signaling, PDGF-BB expression assay, angiogenic morphogenesis assays","journal":"Lab on a chip","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic signaling (PDGF-BB induction via plexin-B1) defined in a 3D functional model, single lab","pmids":["36331411"],"is_preprint":false}],"current_model":"SEMA4D/CD100 is a homodimeric transmembrane semaphorin (structurally a seven-bladed beta-propeller with PSI and Ig-like domains) that signals through three receptors depending on cell context—CD72 on lymphoid cells (switching off SHP-1-mediated negative B cell signaling), plexin-B1 on neurons, endothelial cells, and other non-lymphoid tissues (activating RhoA/ROCK, R-Ras GAP, PI3K/Akt/GSK-3β, and Met pathways), and plexin-B2 on keratinocytes and other epithelia (activating RhoA/Rac1/NF-κB/NLRP3)—and is regulated post-translationally by metalloprotease-mediated ectodomain shedding (via ADAM17, MMP2/9, or MMP14), which is in turn controlled by calmodulin dissociation from the membrane-proximal cytoplasmic domain and by upstream signals including STING activation."},"narrative":{"mechanistic_narrative":"SEMA4D/CD100 is a homodimeric transmembrane semaphorin that functions as a context-dependent ligand coordinating immune regulation, axon guidance, synapse formation, and vascular biology by engaging distinct receptors on different cell types [PMID:11114376, PMID:12958590]. Its ectodomain forms a seven-bladed beta-propeller sema domain with PSI and Ig-like domains, and homodimerization through the propeller top faces both stabilizes the molecule and creates the receptor-binding surface [PMID:12958590]. On lymphoid cells SEMA4D signals through CD72: ligation dephosphorylates CD72 and dissociates the phosphatase SHP-1, relieving negative regulation of B-cell receptor signaling, and CD100 deficiency leaves SHP-1 constitutively bound to CD72 to produce BCR hyporesponsiveness and age-dependent autoimmunity [PMID:11114375, PMID:12882840, PMID:16113236]. In non-lymphoid tissues it acts mainly through plexin-B1, which couples to multiple downstream effectors—the Met tyrosine kinase to drive angiogenesis [PMID:15632204], R-Ras GAP activity that inactivates PI3K/Akt and activates GSK-3β to collapse neuronal growth cones [PMID:16799460], and PDZ-RhoGEF/RhoA/ROCK signaling controlling dendritic spines [PMID:17950529]—while reciprocal regulation by active Rac modulates plexin-B1 surface localization and ligand binding [PMID:11937491]. A third receptor, plexin-B2, mediates epithelial responses, driving γδ T-cell-dependent wound healing through ERK/cofilin [PMID:22902232] and keratinocyte RhoA/Rac1/NF-κB/NLRP3 inflammasome activation in psoriatic inflammation [PMID:28927892]. SEMA4D is regulated post-translationally by metalloprotease-dependent ectodomain shedding that requires Cys674-dependent dimerization and releases a bioactive soluble homodimer [PMID:11254687]; shedding is triggered by calmodulin dissociation from the membrane-proximal cytoplasmic domain upon platelet activation and executed by ADAM17, MMP2/9, or MMP14 depending on cell type and stimulus including STING activation [PMID:23564909, PMID:29618514, PMID:31173811, PMID:34414666]. A germline K849T mutation in the cytosolic domain alters T-cell function and confers susceptibility to cholangitis, establishing a direct genetic link between SEMA4D and immune-mediated disease [PMID:33627483].","teleology":[{"year":2000,"claim":"Establishing that SEMA4D uses CD72 on lymphocytes and plexin-B1 in non-lymphoid tissue defined the founding principle that this semaphorin is a context-dependent ligand with distinct receptors and opposite signaling logics.","evidence":"Expression cloning, binding affinity measurement, and CD100-knockout mice with immune functional assays","pmids":["11114375","12882840","11114376"],"confidence":"High","gaps":["Did not resolve how receptor choice is enforced at the tissue level","Plexin-B2 not yet identified as a third receptor"]},{"year":2000,"claim":"Mapping CD72 dephosphorylation and SHP-1 dissociation answered how SEMA4D regulates lymphocyte signaling, showing it acts as an inhibitory-receptor off-switch.","evidence":"Co-immunoprecipitation and tyrosine dephosphorylation assays in B cells","pmids":["11114375","12882840"],"confidence":"High","gaps":["Did not establish how CD72 ligation triggers SHP-1 release biochemically"]},{"year":2003,"claim":"The crystal structure answered the architectural basis of receptor binding, revealing a seven-bladed beta-propeller sema domain whose dimeric top faces form the ligand surface.","evidence":"X-ray crystallography of residues 1–657 with functional mapping","pmids":["12958590"],"confidence":"High","gaps":["No co-structure with any receptor","Cytoplasmic domain not crystallized"]},{"year":2001,"claim":"Demonstrating metalloprotease-dependent shedding and the Cys674 dimerization requirement explained how a membrane semaphorin generates a diffusible soluble agonist.","evidence":"Metalloprotease inhibition, C674 mutagenesis, and immunoprecipitation in transfected cells","pmids":["11254687"],"confidence":"High","gaps":["Specific sheddase not identified at this stage","Kinase regulating cleavage not defined"]},{"year":2002,"claim":"Showing that plexin-B1 and PAK compete for active Rac, with Rac feeding back on plexin-B1 surface localization, established bidirectional crosstalk between SEMA4D signaling and Rho-family GTPases.","evidence":"Pulldown/binding assays, PAK kinase assays, and dominant-active Rac constructs","pmids":["11937491"],"confidence":"High","gaps":["Did not connect this crosstalk to a defined cellular phenotype"]},{"year":2005,"claim":"Identifying plexin-B1/Met coupling answered how SEMA4D drives angiogenesis, linking it to receptor tyrosine kinase activation.","evidence":"In vitro and in vivo angiogenesis assays with Plexin-B1/Met co-IP and rescue","pmids":["15632204"],"confidence":"High","gaps":["Did not define the structural basis of plexin-B1/Met association"]},{"year":2006,"claim":"Defining plexin-B1 as an R-Ras GAP that inactivates PI3K/Akt and activates GSK-3β/CRMP-2 provided a complete signaling pathway for SEMA4D-induced growth cone collapse.","evidence":"R-Ras GTP-loading, Akt/GSK-3β phosphorylation assays, mutants, and inhibitors in hippocampal neurons","pmids":["16799460"],"confidence":"High","gaps":["Did not address how the same receptor selects GAP versus RhoGEF outputs"]},{"year":2013,"claim":"Showing calmodulin dissociation from the cytoplasmic domain triggers ADAM17 cleavage answered how shedding is signal-coupled in platelets.","evidence":"Co-precipitation, calmodulin inhibitor, peptide competition, and deletion mutagenesis","pmids":["23564909"],"confidence":"High","gaps":["Did not establish whether calmodulin control operates in non-platelet cells"]},{"year":2013,"claim":"Demonstrating PlexinB1-dependent rapid GABAergic synapse assembly extended SEMA4D function from axon repulsion to acute synaptogenesis.","evidence":"Live imaging, PlxnB1-knockout mice, and organotypic epilepsy slice model","pmids":["23699507","24036351"],"confidence":"High","gaps":["Did not define the synaptic effectors recruited downstream of PlexinB1"]},{"year":2012,"claim":"Identifying plexin-B2 on keratinocytes as the receptor for epidermal γδ T-cell function established a third distinct SEMA4D receptor and an ERK/cofilin output.","evidence":"Blocking antibodies, CD100-/- mice, wound healing, and ERK/cofilin assays","pmids":["22902232"],"confidence":"High","gaps":["Did not define structural determinants of plexin-B2 versus plexin-B1 selectivity"]},{"year":2018,"claim":"Showing STING-driven ADAM17 shedding independent of TBK1/IRF3 transcription established that SEMA4D is mobilized as a proinflammatory mediator purely post-translationally.","evidence":"Macrophage secretome mass spectrometry with ADAM17 and TBK1 inhibitor dissection","pmids":["29618514"],"confidence":"High","gaps":["Did not identify the receptor engaged by the shed proinflammatory SEMA4D"]},{"year":2021,"claim":"A germline cytosolic-domain K849T mutation validated in knock-in mice linked SEMA4D directly to a Mendelian immune disorder with cholangitis susceptibility.","evidence":"Whole-exome sequencing, knock-in mice, T-cell assays, and wild-type T-cell transfer rescue","pmids":["33627483"],"confidence":"High","gaps":["Mechanism by which the cytosolic mutation alters forward signaling not resolved"]},{"year":2022,"claim":"Identifying ROR2-mediated PlexinB1 phosphorylation in choroidal pericytes added a co-receptor mechanism for SEMA4D in neovascular disease.","evidence":"Patient samples, CNV mouse models, and PlexinB1 phosphorylation/ROR2 functional studies","pmids":["40121188"],"confidence":"Medium","gaps":["Single study; ROR2/PlexinB1 interaction not reconstituted biochemically"]},{"year":null,"claim":"How a single ligand-receptor pair selects among opposing effector outputs (Met activation, R-Ras GAP, RhoGEF/RhoA, ERK/cofilin) in a cell-type-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking receptor co-factors to effector selection","No receptor co-complex structure","Determinants of plexin-B1 versus plexin-B2 versus plexin-C1 engagement unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,6,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,7,23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,5,11,12]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,15,18,24]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,16,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,9,26]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,10,14]}],"complexes":[],"partners":["CD72","PLXNB1","PLXNB2","CD45","SHP-1","MET","PLXNC1","ADAM17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92854","full_name":"Semaphorin-4D","aliases":["A8","BB18","GR3"],"length_aa":862,"mass_kda":96.2,"function":"Cell surface receptor for PLXNB1 and PLXNB2 that plays an important role in cell-cell signaling (PubMed:20877282). 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RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/17376242","citation_count":22,"is_preprint":false},{"pmid":"24040126","id":"PMC_24040126","title":"Elevated plasma soluble Sema4D/CD100 levels are associated with disease severity in patients of hemorrhagic fever with renal syndrome.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24040126","citation_count":21,"is_preprint":false},{"pmid":"12485616","id":"PMC_12485616","title":"CD100/Sema4D, a lymphocyte semaphorin involved in the regulation of humoral and cellular immune responses.","date":"2003","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12485616","citation_count":20,"is_preprint":false},{"pmid":"26629156","id":"PMC_26629156","title":"Serum Sema4D levels are associated with lumbar spine bone mineral density and bone turnover markers in patients with postmenopausal osteoporosis.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26629156","citation_count":20,"is_preprint":false},{"pmid":"33627483","id":"PMC_33627483","title":"A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis.","date":"2021","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33627483","citation_count":19,"is_preprint":false},{"pmid":"26378166","id":"PMC_26378166","title":"CD8low CD100- T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26378166","citation_count":19,"is_preprint":false},{"pmid":"30981760","id":"PMC_30981760","title":"CD100-plexin-B1 induces epithelial-mesenchymal transition of head and neck squamous cell carcinoma and promotes metastasis.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30981760","citation_count":18,"is_preprint":false},{"pmid":"35794581","id":"PMC_35794581","title":"SEMA4D/PlexinB1 promotes AML progression via activation of PI3K/Akt signaling.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35794581","citation_count":18,"is_preprint":false},{"pmid":"31651222","id":"PMC_31651222","title":"SEMA4D under the posttranscriptional regulation of HuR and miR-4319 boosts cancer progression in esophageal squamous cell carcinoma.","date":"2019","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31651222","citation_count":18,"is_preprint":false},{"pmid":"27614265","id":"PMC_27614265","title":"Sema4D is required in both the adaptive and innate immune responses of contact hypersensitivity.","date":"2016","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27614265","citation_count":17,"is_preprint":false},{"pmid":"32382577","id":"PMC_32382577","title":"Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/32382577","citation_count":17,"is_preprint":false},{"pmid":"17950916","id":"PMC_17950916","title":"A novel role for the semaphorin Sema4D in the induction of allo-responses.","date":"2007","source":"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/17950916","citation_count":17,"is_preprint":false},{"pmid":"36331411","id":"PMC_36331411","title":"Sema4D-plexin-B1 signaling in recruiting dental stem cells for vascular stabilization on a microfluidic platform.","date":"2022","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/36331411","citation_count":16,"is_preprint":false},{"pmid":"24098722","id":"PMC_24098722","title":"Phage display identification of CD100 in human atherosclerotic plaque macrophages and foam cells.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24098722","citation_count":15,"is_preprint":false},{"pmid":"30967271","id":"PMC_30967271","title":"LncRNA LINC01061 sponges miR-612 to regulate the oncogenic role of SEMA4D in cholangiocarcinoma.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30967271","citation_count":15,"is_preprint":false},{"pmid":"37952827","id":"PMC_37952827","title":"Inhibition of Sema4D attenuates pressure overload-induced pathological myocardial hypertrophy via the MAPK/NF-κB/NLRP3 pathways.","date":"2023","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/37952827","citation_count":14,"is_preprint":false},{"pmid":"38129877","id":"PMC_38129877","title":"Schistosome egg-derived extracellular vesicles deliver Sja-miR-71a inhibits host macrophage and neutrophil extracellular traps via targeting Sema4D.","date":"2023","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38129877","citation_count":14,"is_preprint":false},{"pmid":"33258873","id":"PMC_33258873","title":"The emerging roles of semaphorin4D/CD100 in immunological diseases.","date":"2020","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/33258873","citation_count":13,"is_preprint":false},{"pmid":"22606231","id":"PMC_22606231","title":"Placental expression of CD100, CD72 and CD45 is dysregulated in human miscarriage.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22606231","citation_count":13,"is_preprint":false},{"pmid":"34337054","id":"PMC_34337054","title":"SEMA4D Knockdown Attenuates β-Catenin-Dependent Tumor Progression in Colorectal Cancer.","date":"2021","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/34337054","citation_count":13,"is_preprint":false},{"pmid":"40121188","id":"PMC_40121188","title":"Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40121188","citation_count":12,"is_preprint":false},{"pmid":"33776991","id":"PMC_33776991","title":"Soluble Sema4D in Plasma of Head and Neck Squamous Cell Carcinoma Patients Is Associated With Underlying Non-Inflamed Tumor Profile.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33776991","citation_count":12,"is_preprint":false},{"pmid":"33593275","id":"PMC_33593275","title":"CD100 modulates cytotoxicity of CD8+ T cells in patients with acute myocardial infarction.","date":"2021","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33593275","citation_count":12,"is_preprint":false},{"pmid":"30324109","id":"PMC_30324109","title":"CD100 Effects in Macrophages and Its Roles in Atherosclerosis.","date":"2018","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30324109","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50280,"output_tokens":8013,"usd":0.135518,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17534,"output_tokens":4074,"usd":0.09476,"stage2_stop_reason":"end_turn"},"total_usd":0.230278,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CD72 was identified as the lymphocyte receptor for CD100/SEMA4D. CD100 stimulation induced tyrosine dephosphorylation of CD72 and dissociation of the phosphatase SHP-1 from CD72, thereby switching off CD72's negative signaling in B cells.\",\n      \"method\": \"Expression cloning, binding affinity measurements (Kd), co-immunoprecipitation, tyrosine dephosphorylation assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — receptor identified by expression cloning, binding affinities measured, downstream signaling (SHP-1 dissociation) confirmed biochemically, replicated across human and mouse systems\",\n      \"pmids\": [\"11114375\", \"12882840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD100/SEMA4D differentially utilizes two distinct receptors: plexin-B1 in non-lymphoid tissues and CD72 in lymphoid tissues, as demonstrated using CD100-deficient mice.\",\n      \"method\": \"CD100-knockout mouse generation, immune functional assays, genetic epistasis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotypes, replicated finding across multiple papers\",\n      \"pmids\": [\"11114376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of SEMA4D (residues 1–657) revealed a seven-bladed beta-propeller sema domain with unexpected homology to integrins, a PSI domain forming a cysteine knot, and an Ig-like domain. The homodimer is stabilized through interactions between the top faces of the beta-propeller, which also mediates ligand (receptor) binding.\",\n      \"method\": \"X-ray crystallography (crystal structure)\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional mapping of receptor-binding surface\",\n      \"pmids\": [\"12958590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Membrane CD100 is cleaved by a metalloprotease-dependent process to release a soluble homodimeric form. Cysteine 674 in the extracellular domain is required for dimerization, and dimerization is required for proteolytic shedding. A serine kinase inhibitor (staurosporine) enhances cleavage, suggesting the process is regulated by phosphorylation.\",\n      \"method\": \"Metalloprotease inhibitor treatment, site-directed mutagenesis (C674 mutation), cell transfection, immunoprecipitation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of specific residue plus pharmacological inhibition with orthogonal methods in one study\",\n      \"pmids\": [\"11254687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD100 associates with a serine kinase activity in T cells and NK cells, and CD100 itself is a preferred substrate of this kinase. The kinase activity is retained by a fusion protein containing the cytoplasmic domain of CD100.\",\n      \"method\": \"Immunoprecipitation of kinase activity, cytoplasmic domain fusion protein assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase co-immunoprecipitation and cytoplasmic domain construct used, single lab with two orthogonal methods\",\n      \"pmids\": [\"9295286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD100 is physically associated with CD45 (protein tyrosine phosphatase) at the T cell surface, and this association has functional consequences for both molecules including effects on homotypic T cell adhesion. The association is increased during T cell activation.\",\n      \"method\": \"Co-immunoprecipitation, CD45 enzymatic PTPase activity detection, T cell aggregation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and enzymatic assay, single lab\",\n      \"pmids\": [\"8955171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SEMA4D promotes angiogenesis in vitro and in vivo via its high-affinity receptor Plexin-B1, which couples to and activates the Met tyrosine kinase to mediate the angiogenic effects.\",\n      \"method\": \"In vitro angiogenesis assays, in vivo assays, co-immunoprecipitation of Plexin-B1 with Met, functional rescue experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro and in vivo angiogenesis with mechanistic demonstration of Plexin-B1/Met coupling, multiple orthogonal methods\",\n      \"pmids\": [\"15632204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Plexin-B1 and PAK compete for binding to active (GTP-bound) Rac; plexin-B1 inhibits Rac-induced PAK activation. Active Rac enhances Sema4D binding to plexin-B1 and promotes plexin-B1 surface localization, demonstrating bidirectional signaling between Rac and plexin-B1.\",\n      \"method\": \"Pulldown/binding assays, PAK kinase inhibition assay, cell surface binding assays, dominant-active Rac constructs\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal in vitro biochemical assays with functional mutagenesis in a single study\",\n      \"pmids\": [\"11937491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Plexin-B1 functions as an R-Ras GTPase-activating protein (GAP); Sema4D activates this R-Ras GAP activity, which inactivates PI3K, dephosphorylates Akt, and activates GSK-3β, leading to phosphorylation of CRMP-2 and growth cone collapse in hippocampal neurons.\",\n      \"method\": \"R-Ras GTP-loading assay, Akt/GSK-3β phosphorylation assays, constitutively active mutant expression, GSK-3 inhibitor treatment, PI3K activation rescue\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of signaling pathway, multiple mutants and pharmacological inhibitors, mechanistic pathway fully defined\",\n      \"pmids\": [\"16799460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sema4D activates RhoA via plexin-B1's association with PDZ-RhoGEFs, leading to increased dendritic spine density and changes in spine shape in cultured neurons. This effect requires the C-terminal PDZ-RhoGEF-binding domain of plexin-B1 and is blocked by the ROCK inhibitor Y-27632.\",\n      \"method\": \"Exogenous Sema4D application to neurons, RhoA activation assay, ROCK inhibitor treatment, plexin-B1 C-terminal deletion mutant expression\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutagenesis and pharmacological inhibition in neuronal cultures, single lab\",\n      \"pmids\": [\"17950529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sema4D promotes rapid GABAergic synapse assembly in rodent hippocampus via its receptor PlexinB1. Sema4D treatment increases GABAergic synapse density within 30 minutes by recruiting synaptic proteins to both pre- and postsynaptic terminals; this effect is absent in PlxnB1-/- mice.\",\n      \"method\": \"Immunocytochemistry, live imaging of synaptic protein addition, PlxnB1-knockout mice, organotypic slice epilepsy model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse validation plus live imaging and functional electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"23699507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sema4D localizes to synapses as a membrane-bound protein and signals through its extracellular domain in the postsynaptic membrane to promote GABAergic synapse formation, despite being proteolytically cleaved; the membrane-bound form (not shed) is required for this function.\",\n      \"method\": \"Immunolocalization, proteolysis assays, RNAi knockdown, domain-specific functional assays in hippocampal neurons\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization and knockdown with mechanistic dissection of membrane-bound vs. shed form, single lab\",\n      \"pmids\": [\"24036351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEMA4D exodomain shedding in platelets is regulated by calmodulin: the membrane-proximal cytoplasmic domain (Arg762–Lys779) contains a calmodulin-binding site; calmodulin dissociates from this site upon platelet activation, which is sufficient to trigger ADAM17-dependent cleavage and release of the bioactive 120-kDa exodomain fragment.\",\n      \"method\": \"Co-precipitation, calmodulin inhibitor (W7), membrane-permeable peptide competition, deletion mutagenesis of calmodulin-binding domain\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific domain combined with pharmacological inhibitors and peptide competition, mechanistically rigorous single study\",\n      \"pmids\": [\"23564909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STING activation in macrophages triggers ADAM17-mediated shedding of membrane-bound SEMA4D to produce soluble proinflammatory SEMA4D, independently of the TBK1/IRF3 transcriptional pathway (SEMA4D gene expression is not upregulated). This ADAM17-dependent shedding is blocked by the ADAM17 inhibitor TMI-1 but not by the TBK1 inhibitor BX795.\",\n      \"method\": \"Macrophage secretome mass spectrometry, ADAM17 inhibitor (TMI-1) treatment, TBK1 inhibitor (BX795) treatment, western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — pharmacological dissection with two inhibitors, proteomic identification, mechanistic distinction of transcriptional vs. post-translational pathway\",\n      \"pmids\": [\"29618514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sema4D/CD100 is expressed by oligodendrocytes and myelin in the CNS (confirmed by western blot on myelin), is strongly inhibitory for postnatal sensory and cerebellar granule cell axons in stripe assays, and is upregulated transiently in oligodendrocytes at the periphery of spinal cord lesions.\",\n      \"method\": \"Double-labeling immunohistochemistry, western blot, stripe axon-repulsion assay, neuron-oligodendrocyte co-culture, spinal cord lesion model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IHC, WB, functional stripe assay, in vivo lesion model) in a single rigorous study\",\n      \"pmids\": [\"14534257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Soluble CD100 from activated T lymphocytes (sCD100) collapses oligodendrocyte process extensions and triggers apoptosis of immature neural/oligodendrocyte cells, likely through plexin family receptors; this was demonstrated by blocking sCD100 with specific antibodies or adding recombinant sCD100.\",\n      \"method\": \"T lymphocyte-neural cell co-culture, blocking antibody experiments, recombinant sCD100 treatment, apoptosis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue/blockade with antibodies plus recombinant protein, receptor identity not fully resolved\",\n      \"pmids\": [\"14707103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Plexin-B2 on keratinocytes is the CD100 receptor mediating epidermal γδ T cell function in wound healing. CD100 ligation in γδ T cells induced cellular rounding via ERK kinase and cofilin signaling; CD100 deficiency caused defective wound healing due to disrupted γδ T cell response.\",\n      \"method\": \"In vitro blocking antibodies against plexin-B2 or CD100, CD100-/- mice, wound healing assay, ERK/cofilin signaling assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse plus in vitro signaling pathway characterization with multiple orthogonal methods\",\n      \"pmids\": [\"22902232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Soluble CD100 inhibits migration of human monocytes via plexin-C1 (VESPR/CD232), while on immature dendritic cells (which downregulate plexin-C1 and upregulate plexin-B1 during differentiation), sCD100 acts through plexin-B1 to inhibit migration and modulate cytokine production.\",\n      \"method\": \"Migration assays with competition/blocking experiments, flow cytometry of receptor expression during monocyte-to-DC differentiation, cytokine assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identity established by competition assays with specific antibodies, single lab, two cell types\",\n      \"pmids\": [\"15746246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Only the dimeric form of soluble CD100 inhibits spontaneous and chemokine-induced migration of human monocytes and B cell-lineage cells. CD100 and H-SemaIII act through the same receptor on immune cells (not neuropilin-1); one anti-CD100 mAb abolishes the inhibitory effect of both semaphorins.\",\n      \"method\": \"Cell migration assay, use of monomeric vs. dimeric soluble CD100, antibody blocking, cross-competition with H-SemaIII\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional migration assays with antibody blocking and cross-competition, receptor partially defined (not neuropilin-1), single lab\",\n      \"pmids\": [\"11254688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sema4D promotes iNOS expression in microglia through plexin-B1 (not CD72); during EAE, Sema4D-plexin-B1 interactions in CNS-resident cells (microglia) contribute to neuroinflammation, as adoptive transfer of MOG-specific T cells into plexin-B1-deficient mice significantly attenuated EAE.\",\n      \"method\": \"Primary microglia cultures, plexin-B1-/- and CD72-/- mice, bone marrow chimeras, adoptive T cell transfer, EAE model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockout models including chimeras and adoptive transfer, mechanistic dissection of receptor specificity (plexin-B1 vs. CD72)\",\n      \"pmids\": [\"20038643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SEMA4D signaling disrupts endothelial tight junctions forming the BBB, inhibits migration and differentiation of oligodendrocyte precursor cells (OPCs), and induces glial activation; anti-SEMA4D antibody reverses inhibitory effects on OPC survival/differentiation in vitro and preserves BBB integrity and myelination in EAE models in vivo.\",\n      \"method\": \"In vitro OPC differentiation assay with recombinant SEMA4D and antibody reversal, multiple rodent EAE models with anti-SEMA4D antibody treatment, MRI/histology\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro mechanistic rescue plus multiple in vivo models with defined cellular readouts\",\n      \"pmids\": [\"25461192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sema4D deficiency in ApoE-/- mice reduces intimal neovascularization and plaque macrophage infiltration, demonstrating that Sema4D (expressed by infiltrating lymphoid cells) promotes atherosclerotic plaque angiogenesis via plexin-B1 on neovascular endothelial cells.\",\n      \"method\": \"Sema4D/ApoE double-knockout mouse model, lipid staining, immunohistochemistry for plexin-B1 and CD31/isolectin B4 (neovascularization markers), macrophage counting\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic deletion model with defined vascular phenotype, single lab\",\n      \"pmids\": [\"20514420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sema4D deficiency reduces platelet hyperreactivity in dyslipidemia and protects against atherosclerosis development; loss of Sema4D expression reduces platelet accumulation after arterial injury and platelet aggregation on collagen under flow.\",\n      \"method\": \"sema4D-/-/LDLR-/- double-knockout mice on high-fat diet, platelet accumulation assay in vivo and ex vivo, platelet aggregation under flow\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic deletion with defined platelet functional phenotype, single lab\",\n      \"pmids\": [\"19390055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD100/Sema4D regulates BCR signaling sensitivity by preventing CD72 from associating with the BCR. In the absence of CD100, SHP-1 constitutively associates with CD72, causing BCR hyporesponsiveness; with age, CD100-deficient mice accumulate marginal zone B cells and develop autoimmunity.\",\n      \"method\": \"CD100-knockout mice, BCR signaling assays, co-immunoprecipitation of CD72 with BCR complex, B cell subset analysis\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with co-IP mechanistic follow-up, single lab\",\n      \"pmids\": [\"16113236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MMP2 and MMP9 mediate shedding of membrane-bound CD100 from T cells to generate soluble CD100; patients with chronic HBV had lower serum MMP2 correlated with lower sCD100. Therapeutic sCD100 activated DCs and liver sinusoidal endothelial cells, enhanced HBV-specific CD8 T cell responses via CD72, and accelerated HBV clearance; blockade of CD72 attenuated the intrahepatic anti-HBV CD8 T cell response.\",\n      \"method\": \"MMP2/9 inhibition in vivo, recombinant sCD100 treatment, anti-CD72 blockade, DC maturation assay, HBV clearance assay\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mechanistic experiments with defined immunological readouts, identification of MMP2/9 as sheddases, single lab\",\n      \"pmids\": [\"31173811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sema4D/PlexinB1 signaling induces endothelial cell dysfunction in diabetic retinopathy via mDIA1, mediated through Src-dependent VE-cadherin dysfunction. Genetic disruption of Sema4D/PlexinB1 or anti-Sema4D antibody reduced pericyte loss and vascular leakage in a streptozotocin model.\",\n      \"method\": \"Genetic Sema4D/PlexinB1 disruption, intravitreal anti-Sema4D injection, endothelial cell dysfunction assays, Src-VE-cadherin phosphorylation assays, in vivo OIR/STZ models\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disruption plus antibody blockade, mechanistic pathway (mDIA1-Src-VE-cadherin) defined with multiple in vitro and in vivo methods\",\n      \"pmids\": [\"31943789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD100-PlexinB2 signaling in keratinocytes promotes psoriatic inflammation by activating RhoA and Rac1 GTPases, which stimulate NF-κB signaling and activate the NLRP3 inflammasome, leading to production of CXCL-1, CCL-20, IL-1β, and IL-18.\",\n      \"method\": \"siRNA knockdown of PlxnB2, soluble CD100 stimulation, RhoA/Rac1 activation assays, NF-κB reporter assays, NLRP3 inflammasome activation assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathway assays in keratinocytes, single lab\",\n      \"pmids\": [\"28927892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD45 (protein tyrosine phosphatase) switches its association with CD100 depending on B cell differentiation stage; in pre-B, activated B, and pre-plasma cell stages CD45 is the main PTP associated with CD100, but at the terminal plasma cell stage, CD45 is no longer the associated PTP, indicating a switch in CD100-associated phosphatase.\",\n      \"method\": \"Cell sorting, immunoprecipitation, immunodepletion, in vitro enzymatic PTP activity assay, western blotting of B cell lines and primary sorted B cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity measurement plus immunodepletion, single lab with multiple cell types\",\n      \"pmids\": [\"10648410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD100 on γδ intraepithelial lymphocytes signals to plexin-B2 on colonocytes; CD100-/- mice show exacerbated DSS-induced colitis because γδ IEL fail to produce KGF-1 in response to epithelial damage. Administration of recombinant KGF-1 to CD100-/- mice rescues the colitis phenotype.\",\n      \"method\": \"CD100-/- mice, DSS colitis model, KGF-1 production assay, recombinant KGF-1 rescue experiment\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with defined cellular mechanism and cytokine rescue, single lab\",\n      \"pmids\": [\"23695512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A germline heterozygous K849T missense mutation in the cytosolic domain of CD100/SEMA4D causes altered T cell function (increased proliferation and impaired IFN-γ production). Knock-in mice with the homologous mutation show the same T cell IFN-γ impairment and increased susceptibility to DDC diet-induced cholangitis; transfer of wild-type T cells attenuates cholangitis.\",\n      \"method\": \"Whole-exome sequencing, knock-in mouse generation, T cell functional assays, DDC-diet cholangitis model, wild-type T cell transfer rescue\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline mutation identified, validated in knock-in mouse model with in vivo rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"33627483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sema4D on CD8+ T cells interacts with PlexinB1 on choroidal pericytes in age-related macular degeneration; this interaction leads to ROR2-mediated PlexinB1 phosphorylation and pericyte activation, disrupting vascular homeostasis and promoting choroidal neovascularization.\",\n      \"method\": \"Patient-derived samples, mouse CNV models, PlexinB1 phosphorylation assays, ROR2 functional studies, anti-Sema4D antibody treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic signaling pathway in vivo and in vitro, ROR2 phosphorylation of PlexinB1 identified, single study\",\n      \"pmids\": [\"40121188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD100 expressed on NK cells enhances cytotoxicity and IFN-γ secretion by binding to CD72 on target cells, increasing adhesion between NK cells and their targets rather than directly mediating killing.\",\n      \"method\": \"NK cell-target cell co-culture, CD100/CD72 blocking antibodies, adhesion assays, cytotoxicity assays, IFN-γ measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antibody blocking with multiple readouts, single lab\",\n      \"pmids\": [\"17786190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MMP14 mediates membrane CD100 shedding in macrophages in response to PLXNB2-containing exosomes derived from OVA-challenged airway epithelial cells. Knockdown of Mmp14 in macrophages prevents CD100 cleavage and reduces pro-inflammatory chemokine transcription.\",\n      \"method\": \"Exosome isolation and aspiration, MMP14 knockdown in macrophages, CD100 shedding assay, chemokine transcription analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific sheddase (MMP14) identified by knockdown with functional readout, single lab\",\n      \"pmids\": [\"34414666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sema4D facilitates recruitment of dental stem cells (SHED) as mural cells during angiogenesis by acting on endothelial-plexin-B1 and inducing expression of PDGF-BB, a mural cell recruitment factor, in a 3D microfluidic platform.\",\n      \"method\": \"3D biomimetic microfluidic device, pharmacological and genetic manipulation of Sema4D/plexin-B1 signaling, PDGF-BB expression assay, angiogenic morphogenesis assays\",\n      \"journal\": \"Lab on a chip\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic signaling (PDGF-BB induction via plexin-B1) defined in a 3D functional model, single lab\",\n      \"pmids\": [\"36331411\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEMA4D/CD100 is a homodimeric transmembrane semaphorin (structurally a seven-bladed beta-propeller with PSI and Ig-like domains) that signals through three receptors depending on cell context—CD72 on lymphoid cells (switching off SHP-1-mediated negative B cell signaling), plexin-B1 on neurons, endothelial cells, and other non-lymphoid tissues (activating RhoA/ROCK, R-Ras GAP, PI3K/Akt/GSK-3β, and Met pathways), and plexin-B2 on keratinocytes and other epithelia (activating RhoA/Rac1/NF-κB/NLRP3)—and is regulated post-translationally by metalloprotease-mediated ectodomain shedding (via ADAM17, MMP2/9, or MMP14), which is in turn controlled by calmodulin dissociation from the membrane-proximal cytoplasmic domain and by upstream signals including STING activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMA4D/CD100 is a homodimeric transmembrane semaphorin that functions as a context-dependent ligand coordinating immune regulation, axon guidance, synapse formation, and vascular biology by engaging distinct receptors on different cell types [#1, #2]. Its ectodomain forms a seven-bladed beta-propeller sema domain with PSI and Ig-like domains, and homodimerization through the propeller top faces both stabilizes the molecule and creates the receptor-binding surface [#2]. On lymphoid cells SEMA4D signals through CD72: ligation dephosphorylates CD72 and dissociates the phosphatase SHP-1, relieving negative regulation of B-cell receptor signaling, and CD100 deficiency leaves SHP-1 constitutively bound to CD72 to produce BCR hyporesponsiveness and age-dependent autoimmunity [#0, #23]. In non-lymphoid tissues it acts mainly through plexin-B1, which couples to multiple downstream effectors—the Met tyrosine kinase to drive angiogenesis [#6], R-Ras GAP activity that inactivates PI3K/Akt and activates GSK-3β to collapse neuronal growth cones [#8], and PDZ-RhoGEF/RhoA/ROCK signaling controlling dendritic spines [#9]—while reciprocal regulation by active Rac modulates plexin-B1 surface localization and ligand binding [#7]. A third receptor, plexin-B2, mediates epithelial responses, driving γδ T-cell-dependent wound healing through ERK/cofilin [#16] and keratinocyte RhoA/Rac1/NF-κB/NLRP3 inflammasome activation in psoriatic inflammation [#26]. SEMA4D is regulated post-translationally by metalloprotease-dependent ectodomain shedding that requires Cys674-dependent dimerization and releases a bioactive soluble homodimer [#3]; shedding is triggered by calmodulin dissociation from the membrane-proximal cytoplasmic domain upon platelet activation and executed by ADAM17, MMP2/9, or MMP14 depending on cell type and stimulus including STING activation [#12, #13, #24, #32]. A germline K849T mutation in the cytosolic domain alters T-cell function and confers susceptibility to cholangitis, establishing a direct genetic link between SEMA4D and immune-mediated disease [#29].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that SEMA4D uses CD72 on lymphocytes and plexin-B1 in non-lymphoid tissue defined the founding principle that this semaphorin is a context-dependent ligand with distinct receptors and opposite signaling logics.\",\n      \"evidence\": \"Expression cloning, binding affinity measurement, and CD100-knockout mice with immune functional assays\",\n      \"pmids\": [\"11114375\", \"12882840\", \"11114376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how receptor choice is enforced at the tissue level\", \"Plexin-B2 not yet identified as a third receptor\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping CD72 dephosphorylation and SHP-1 dissociation answered how SEMA4D regulates lymphocyte signaling, showing it acts as an inhibitory-receptor off-switch.\",\n      \"evidence\": \"Co-immunoprecipitation and tyrosine dephosphorylation assays in B cells\",\n      \"pmids\": [\"11114375\", \"12882840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how CD72 ligation triggers SHP-1 release biochemically\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The crystal structure answered the architectural basis of receptor binding, revealing a seven-bladed beta-propeller sema domain whose dimeric top faces form the ligand surface.\",\n      \"evidence\": \"X-ray crystallography of residues 1–657 with functional mapping\",\n      \"pmids\": [\"12958590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure with any receptor\", \"Cytoplasmic domain not crystallized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating metalloprotease-dependent shedding and the Cys674 dimerization requirement explained how a membrane semaphorin generates a diffusible soluble agonist.\",\n      \"evidence\": \"Metalloprotease inhibition, C674 mutagenesis, and immunoprecipitation in transfected cells\",\n      \"pmids\": [\"11254687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific sheddase not identified at this stage\", \"Kinase regulating cleavage not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that plexin-B1 and PAK compete for active Rac, with Rac feeding back on plexin-B1 surface localization, established bidirectional crosstalk between SEMA4D signaling and Rho-family GTPases.\",\n      \"evidence\": \"Pulldown/binding assays, PAK kinase assays, and dominant-active Rac constructs\",\n      \"pmids\": [\"11937491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect this crosstalk to a defined cellular phenotype\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying plexin-B1/Met coupling answered how SEMA4D drives angiogenesis, linking it to receptor tyrosine kinase activation.\",\n      \"evidence\": \"In vitro and in vivo angiogenesis assays with Plexin-B1/Met co-IP and rescue\",\n      \"pmids\": [\"15632204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of plexin-B1/Met association\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining plexin-B1 as an R-Ras GAP that inactivates PI3K/Akt and activates GSK-3β/CRMP-2 provided a complete signaling pathway for SEMA4D-induced growth cone collapse.\",\n      \"evidence\": \"R-Ras GTP-loading, Akt/GSK-3β phosphorylation assays, mutants, and inhibitors in hippocampal neurons\",\n      \"pmids\": [\"16799460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how the same receptor selects GAP versus RhoGEF outputs\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing calmodulin dissociation from the cytoplasmic domain triggers ADAM17 cleavage answered how shedding is signal-coupled in platelets.\",\n      \"evidence\": \"Co-precipitation, calmodulin inhibitor, peptide competition, and deletion mutagenesis\",\n      \"pmids\": [\"23564909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether calmodulin control operates in non-platelet cells\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating PlexinB1-dependent rapid GABAergic synapse assembly extended SEMA4D function from axon repulsion to acute synaptogenesis.\",\n      \"evidence\": \"Live imaging, PlxnB1-knockout mice, and organotypic epilepsy slice model\",\n      \"pmids\": [\"23699507\", \"24036351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the synaptic effectors recruited downstream of PlexinB1\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying plexin-B2 on keratinocytes as the receptor for epidermal γδ T-cell function established a third distinct SEMA4D receptor and an ERK/cofilin output.\",\n      \"evidence\": \"Blocking antibodies, CD100-/- mice, wound healing, and ERK/cofilin assays\",\n      \"pmids\": [\"22902232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define structural determinants of plexin-B2 versus plexin-B1 selectivity\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing STING-driven ADAM17 shedding independent of TBK1/IRF3 transcription established that SEMA4D is mobilized as a proinflammatory mediator purely post-translationally.\",\n      \"evidence\": \"Macrophage secretome mass spectrometry with ADAM17 and TBK1 inhibitor dissection\",\n      \"pmids\": [\"29618514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the receptor engaged by the shed proinflammatory SEMA4D\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A germline cytosolic-domain K849T mutation validated in knock-in mice linked SEMA4D directly to a Mendelian immune disorder with cholangitis susceptibility.\",\n      \"evidence\": \"Whole-exome sequencing, knock-in mice, T-cell assays, and wild-type T-cell transfer rescue\",\n      \"pmids\": [\"33627483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the cytosolic mutation alters forward signaling not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying ROR2-mediated PlexinB1 phosphorylation in choroidal pericytes added a co-receptor mechanism for SEMA4D in neovascular disease.\",\n      \"evidence\": \"Patient samples, CNV mouse models, and PlexinB1 phosphorylation/ROR2 functional studies\",\n      \"pmids\": [\"40121188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study; ROR2/PlexinB1 interaction not reconstituted biochemically\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single ligand-receptor pair selects among opposing effector outputs (Met activation, R-Ras GAP, RhoGEF/RhoA, ERK/cofilin) in a cell-type-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking receptor co-factors to effector selection\", \"No receptor co-complex structure\", \"Determinants of plexin-B1 versus plexin-B2 versus plexin-C1 engagement unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 6, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 7, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5, 11, 12]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 15, 18, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 16, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 9, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 10, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD72\", \"PLXNB1\", \"PLXNB2\", \"CD45\", \"SHP-1\", \"MET\", \"PLXNC1\", \"ADAM17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}