Affinage

SEMA4D

Semaphorin-4D · UniProt Q92854

Length
862 aa
Mass
96.2 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    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

    PMID:11114375 PMID:11114376 PMID:12882840

    Open questions at the time
    • Did not resolve how receptor choice is enforced at the tissue level
    • Plexin-B2 not yet identified as a third receptor
  2. 2000 High

    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

    PMID:11114375 PMID:12882840

    Open questions at the time
    • Did not establish how CD72 ligation triggers SHP-1 release biochemically
  3. 2003 High

    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

    PMID:12958590

    Open questions at the time
    • No co-structure with any receptor
    • Cytoplasmic domain not crystallized
  4. 2001 High

    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

    PMID:11254687

    Open questions at the time
    • Specific sheddase not identified at this stage
    • Kinase regulating cleavage not defined
  5. 2002 High

    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

    PMID:11937491

    Open questions at the time
    • Did not connect this crosstalk to a defined cellular phenotype
  6. 2005 High

    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

    PMID:15632204

    Open questions at the time
    • Did not define the structural basis of plexin-B1/Met association
  7. 2006 High

    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

    PMID:16799460

    Open questions at the time
    • Did not address how the same receptor selects GAP versus RhoGEF outputs
  8. 2013 High

    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

    PMID:23564909

    Open questions at the time
    • Did not establish whether calmodulin control operates in non-platelet cells
  9. 2013 High

    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

    PMID:23699507 PMID:24036351

    Open questions at the time
    • Did not define the synaptic effectors recruited downstream of PlexinB1
  10. 2012 High

    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

    PMID:22902232

    Open questions at the time
    • Did not define structural determinants of plexin-B2 versus plexin-B1 selectivity
  11. 2018 High

    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

    PMID:29618514

    Open questions at the time
    • Did not identify the receptor engaged by the shed proinflammatory SEMA4D
  12. 2021 High

    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

    PMID:33627483

    Open questions at the time
    • Mechanism by which the cytosolic mutation alters forward signaling not resolved
  13. 2022 Medium

    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

    PMID:40121188

    Open questions at the time
    • Single study; ROR2/PlexinB1 interaction not reconstituted biochemically

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3
Partners
ADAM17CD45CD72METPLXNB1PLXNB2PLXNC1SHP-1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Expression cloning, binding affinity measurements (Kd), co-immunoprecipitation, tyrosine dephosphorylation assay Immunity High 11114375 12882840
2000 CD100/SEMA4D differentially utilizes two distinct receptors: plexin-B1 in non-lymphoid tissues and CD72 in lymphoid tissues, as demonstrated using CD100-deficient mice. CD100-knockout mouse generation, immune functional assays, genetic epistasis Immunity High 11114376
2003 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. X-ray crystallography (crystal structure) Nature structural biology High 12958590
2001 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. Metalloprotease inhibitor treatment, site-directed mutagenesis (C674 mutation), cell transfection, immunoprecipitation Journal of immunology High 11254687
1997 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. Immunoprecipitation of kinase activity, cytoplasmic domain fusion protein assay The Journal of biological chemistry Medium 9295286
1996 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. Co-immunoprecipitation, CD45 enzymatic PTPase activity detection, T cell aggregation assay Journal of immunology Medium 8955171
2005 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. In vitro angiogenesis assays, in vivo assays, co-immunoprecipitation of Plexin-B1 with Met, functional rescue experiments Blood High 15632204
2002 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. Pulldown/binding assays, PAK kinase inhibition assay, cell surface binding assays, dominant-active Rac constructs Genes & development High 11937491
2006 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. R-Ras GTP-loading assay, Akt/GSK-3β phosphorylation assays, constitutively active mutant expression, GSK-3 inhibitor treatment, PI3K activation rescue EMBO reports High 16799460
2007 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. Exogenous Sema4D application to neurons, RhoA activation assay, ROCK inhibitor treatment, plexin-B1 C-terminal deletion mutant expression Neuroscience letters Medium 17950529
2013 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. Immunocytochemistry, live imaging of synaptic protein addition, PlxnB1-knockout mice, organotypic slice epilepsy model The Journal of neuroscience High 23699507
2013 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. Immunolocalization, proteolysis assays, RNAi knockdown, domain-specific functional assays in hippocampal neurons Molecular and cellular neurosciences Medium 24036351
2013 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. Co-precipitation, calmodulin inhibitor (W7), membrane-permeable peptide competition, deletion mutagenesis of calmodulin-binding domain Blood High 23564909
2018 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. Macrophage secretome mass spectrometry, ADAM17 inhibitor (TMI-1) treatment, TBK1 inhibitor (BX795) treatment, western blot The Journal of biological chemistry High 29618514
2003 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. Double-labeling immunohistochemistry, western blot, stripe axon-repulsion assay, neuron-oligodendrocyte co-culture, spinal cord lesion model The Journal of neuroscience High 14534257
2004 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. T lymphocyte-neural cell co-culture, blocking antibody experiments, recombinant sCD100 treatment, apoptosis assays Journal of immunology Medium 14707103
2012 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. In vitro blocking antibodies against plexin-B2 or CD100, CD100-/- mice, wound healing assay, ERK/cofilin signaling assays Immunity High 22902232
2005 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. Migration assays with competition/blocking experiments, flow cytometry of receptor expression during monocyte-to-DC differentiation, cytokine assays International immunology Medium 15746246
2001 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. Cell migration assay, use of monomeric vs. dimeric soluble CD100, antibody blocking, cross-competition with H-SemaIII Journal of immunology Medium 11254688
2009 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. Primary microglia cultures, plexin-B1-/- and CD72-/- mice, bone marrow chimeras, adoptive T cell transfer, EAE model Journal of immunology High 20038643
2014 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. In vitro OPC differentiation assay with recombinant SEMA4D and antibody reversal, multiple rodent EAE models with anti-SEMA4D antibody treatment, MRI/histology Neurobiology of disease High 25461192
2009 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. Sema4D/ApoE double-knockout mouse model, lipid staining, immunohistochemistry for plexin-B1 and CD31/isolectin B4 (neovascularization markers), macrophage counting International journal of molecular medicine Medium 20514420
2009 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. sema4D-/-/LDLR-/- double-knockout mice on high-fat diet, platelet accumulation assay in vivo and ex vivo, platelet aggregation under flow Arteriosclerosis, thrombosis, and vascular biology Medium 19390055
2005 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. CD100-knockout mice, BCR signaling assays, co-immunoprecipitation of CD72 with BCR complex, B cell subset analysis International immunology Medium 16113236
2019 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. MMP2/9 inhibition in vivo, recombinant sCD100 treatment, anti-CD72 blockade, DC maturation assay, HBV clearance assay Journal of hepatology Medium 31173811
2020 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. Genetic Sema4D/PlexinB1 disruption, intravitreal anti-Sema4D injection, endothelial cell dysfunction assays, Src-VE-cadherin phosphorylation assays, in vivo OIR/STZ models EMBO molecular medicine High 31943789
2017 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. siRNA knockdown of PlxnB2, soluble CD100 stimulation, RhoA/Rac1 activation assays, NF-κB reporter assays, NLRP3 inflammasome activation assays The Journal of investigative dermatology Medium 28927892
2000 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. Cell sorting, immunoprecipitation, immunodepletion, in vitro enzymatic PTP activity assay, western blotting of B cell lines and primary sorted B cells Blood Medium 10648410
2013 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. CD100-/- mice, DSS colitis model, KGF-1 production assay, recombinant KGF-1 rescue experiment Mucosal immunology Medium 23695512
2021 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. Whole-exome sequencing, knock-in mouse generation, T cell functional assays, DDC-diet cholangitis model, wild-type T cell transfer rescue Science translational medicine High 33627483
2022 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. Patient-derived samples, mouse CNV models, PlexinB1 phosphorylation assays, ROR2 functional studies, anti-Sema4D antibody treatment Nature communications Medium 40121188
2007 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. NK cell-target cell co-culture, CD100/CD72 blocking antibodies, adhesion assays, cytotoxicity assays, IFN-γ measurement PloS one Medium 17786190
2018 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. Exosome isolation and aspiration, MMP14 knockdown in macrophages, CD100 shedding assay, chemokine transcription analysis Journal of cellular and molecular medicine Medium 34414666
2022 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. 3D biomimetic microfluidic device, pharmacological and genetic manipulation of Sema4D/plexin-B1 signaling, PDGF-BB expression assay, angiogenic morphogenesis assays Lab on a chip Medium 36331411

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 296 11114375
1996 Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proceedings of the National Academy of Sciences of the United States of America 232 8876214
2003 The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. The Journal of neuroscience : the official journal of the Society for Neuroscience 224 14534257
2000 The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 220 11114376
2008 Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. The Journal of experimental medicine 219 18559453
2005 Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 215 15632204
2004 CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival. Blood 172 15613544
2001 Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration. Journal of immunology (Baltimore, Md. : 1950) 136 11254688
2012 The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function. Immunity 135 22902232
2002 CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes. Blood 132 12406905
2003 The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nature structural biology 131 12958590
2002 Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 129 12133937
2001 Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis. Journal of immunology (Baltimore, Md. : 1950) 118 11254687
2006 Sema4D/plexin-B1 activates GSK-3beta through R-Ras GAP activity, inducing growth cone collapse. EMBO reports 110 16799460
2001 Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses. Blood 108 11369643
2002 The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding. Genes & development 103 11937491
2009 Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950) 100 20038643
2014 SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiology of disease 95 25461192
2001 The CD100-CD72 interaction: a novel mechanism of immune regulation. Trends in immunology 95 11738997
2010 Roles of Sema4D and Plexin-B1 in tumor progression. Molecular cancer 94 20858260
2004 Semaphorin CD100 from activated T lymphocytes induces process extension collapse in oligodendrocytes and death of immature neural cells. Journal of immunology (Baltimore, Md. : 1950) 86 14707103
1998 CD100 is a leukocyte semaphorin. Cellular and molecular life sciences : CMLS 85 9849618
2018 VEGF and SEMA4D have synergistic effects on the promotion of angiogenesis in epithelial ovarian cancer. Cellular & molecular biology letters 83 29308068
2003 Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses. International immunology 83 12882840
2005 Soluble CD100 functions on human monocytes and immature dendritic cells require plexin C1 and plexin B1, respectively. International immunology 79 15746246
2004 Sema4D stimulates axonal outgrowth of embryonic DRG sensory neurones. Genes to cells : devoted to molecular & cellular mechanisms 72 15330859
2020 Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in diabetic retinopathy. EMBO molecular medicine 70 31943789
2017 CD100-Plexin-B2 Promotes the Inflammation in Psoriasis by Activating NF-κB and the Inflammasome in Keratinocytes. The Journal of investigative dermatology 69 28927892
2004 Plexin-B family members demonstrate non-redundant expression patterns in the developing mouse nervous system: an anatomical basis for morphogenetic effects of Sema4D during development. The European journal of neuroscience 69 15147296
2015 Soluble SEMA4D/CD100: A novel immunoregulator in infectious and inflammatory diseases. Clinical immunology (Orlando, Fla.) 64 26732857
1996 CD100 is associated with CD45 at the surface of human T lymphocytes. Role in T cell homotypic adhesion. Journal of immunology (Baltimore, Md. : 1950) 63 8955171
2019 CD Maps-Dynamic Profiling of CD1-CD100 Surface Expression on Human Leukocyte and Lymphocyte Subsets. Frontiers in immunology 55 31708916
2009 Disruption of SEMA4D ameliorates platelet hypersensitivity in dyslipidemia and confers protection against the development of atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 50 19390055
1995 Activation signals are delivered through two distinct epitopes of CD100, a unique 150 kDa human lymphocyte surface structure previously defined by BB18 mAb. International immunology 50 7718506
2022 Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nature medicine 49 35941373
1997 The human semaphorin-like leukocyte cell surface molecule CD100 associates with a serine kinase activity. The Journal of biological chemistry 48 9295286
2001 Enhanced immune responses in transgenic mice expressing a truncated form of the lymphocyte semaphorin CD100. Journal of immunology (Baltimore, Md. : 1950) 46 11591755
2018 The role of sema4D in vasculogenic mimicry formation in non-small cell lung cancer and the underlying mechanisms. International journal of cancer 45 30374974
2015 Generation and preclinical characterization of an antibody specific for SEMA4D. mAbs 45 26431358
2013 The class 4 semaphorin Sema4D promotes the rapid assembly of GABAergic synapses in rodent hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 23699507
2013 Protection against colitis by CD100-dependent modulation of intraepithelial γδ T lymphocyte function. Mucosal immunology 41 23695512
2011 Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth. The Journal of investigative dermatology 41 22189792
2005 Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment. International immunology 41 16113236
2018 Sema4D/PlexinB1 inhibition ameliorates blood-brain barrier damage and improves outcome after stroke in rats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 38 29242274
2006 CD100 enhances dendritic cell and CD4+ cell activation leading to pathogenetic humoral responses and immune complex glomerulonephritis. Journal of immunology (Baltimore, Md. : 1950) 37 16920982
2019 MMP2/MMP9-mediated CD100 shedding is crucial for inducing intrahepatic anti-HBV CD8 T cell responses and HBV clearance. Journal of hepatology 34 31173811
2011 Expansion of CD8+ T cells lacking Sema4D/CD100 during HIV-1 infection identifies a subset of T cells with decreased functional capacity. Blood 34 22134167
2003 Structure and function of the immune semaphorin CD100/SEMA4D. Critical reviews in immunology 34 12906260
2015 CD100 and plexins B2 and B1 mediate monocyte-endothelial cell adhesion and might take part in atherogenesis. Molecular immunology 33 26275342
2000 Switch in the protein tyrosine phosphatase associated with human CD100 semaphorin at terminal B-cell differentiation stage. Blood 33 10648410
2015 Nonclinical Safety Evaluation of VX15/2503, a Humanized IgG4 Anti-SEMA4D Antibody. Molecular cancer therapeutics 32 25657333
2010 Deletion of Sema4D gene reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. International journal of molecular medicine 31 20514420
2009 Endogenous CD100 promotes glomerular injury and macrophage recruitment in experimental crescentic glomerulonephritis. Immunology 31 19689741
2021 circ_NRIP1 is oncogenic in malignant development of esophageal squamous cell carcinoma (ESCC) via miR-595/SEMA4D axis and PI3K/AKT pathway. Cancer cell international 29 33957921
2019 Sema4D expression and secretion are increased by HIF-1α and inhibit osteogenesis in bone metastases of lung cancer. Clinical & experimental metastasis 29 30617444
2013 Identification of a calmodulin-binding domain in Sema4D that regulates its exodomain shedding in platelets. Blood 29 23564909
2009 Sema4D deficiency results in an increase in the number of oligodendrocytes in healthy and injured mouse brains. Journal of neuroscience research 29 19472224
2007 CD100 on NK cells enhance IFNgamma secretion and killing of target cells expressing CD72. PloS one 29 17786190
1998 The leukocyte semaphorin CD100 is expressed in most T-cell, but few B-cell, non-Hodgkin's lymphomas. The American journal of pathology 29 9665486
2007 Sema4D-plexin-B1 implicated in regulation of dendritic spine density through RhoA/ROCK pathway. Neuroscience letters 28 17950529
2018 Promotion of Sema4D expression by tumor-associated macrophages: Significance in gastric carcinoma. World journal of gastroenterology 27 29434448
2015 Effect of Sema4D on microglial function in middle cerebral artery occlusion mice. Glia 27 26202989
2015 Role of inhibition of osteogenesis function by Sema4D/Plexin-B1 signaling pathway in skeletal fluorosis in vitro. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 27 26489627
2013 Sema4D localizes to synapses and regulates GABAergic synapse development as a membrane-bound molecule in the mammalian hippocampus. Molecular and cellular neurosciences 27 24036351
2020 Insufficient CD100 shedding contributes to suppression of CD8+ T-cell activity in non-small cell lung cancer. Immunology 26 32149403
2016 The role of Sema4D/CD100 as a therapeutic target for tumor microenvironments and for autoimmune, neuroimmune and bone diseases. Expert opinion on therapeutic targets 26 26732941
2020 Effects of NRP1 on angiogenesis and vascular maturity in endothelial cells are dependent on the expression of SEMA4D. International journal of molecular medicine 25 32945351
2024 Fibroblasts with high matrix metalloproteinase 2 expression regulate CD8+ T-cell residency and inflammation via CD100 in psoriasis. The British journal of dermatology 24 38752329
2018 Activation of stimulator of interferon genes (STING) induces ADAM17-mediated shedding of the immune semaphorin SEMA4D. The Journal of biological chemistry 24 29618514
2011 Peripheral blood lymphocytes analysis detects CD100/SEMA4D alteration in systemic sclerosis patients. Autoimmunity 24 21244334
2018 CD72/CD100 and PD-1/PD-L1 markers are increased on T and B cells in HIV-1+ viremic individuals, and CD72/CD100 axis is correlated with T-cell exhaustion. PloS one 23 30161254
2017 Intact CD100-CD72 Interaction Necessary for TCR-Induced T Cell Proliferation. Frontiers in immunology 23 28713384
2014 Sema4D knockdown in oligodendrocytes promotes functional recovery after spinal cord injury. Cell biochemistry and biophysics 23 23949850
2013 Increased levels of plasma soluble Sema4D in patients with heart failure. PloS one 23 23741311
2009 Involvement of Sema4D in the control of microglia activation. Neurochemistry international 23 19467284
2021 Increased airway epithelial cell-derived exosomes activate macrophage-mediated allergic inflammation via CD100 shedding. Journal of cellular and molecular medicine 22 34414666
2007 Semaphorin-4D (Sema-4D), the Plexin-B1 ligand, is involved in mouse ovary follicular development. Reproductive biology and endocrinology : RB&E 22 17376242
2013 Elevated plasma soluble Sema4D/CD100 levels are associated with disease severity in patients of hemorrhagic fever with renal syndrome. PloS one 21 24040126
2015 Serum Sema4D levels are associated with lumbar spine bone mineral density and bone turnover markers in patients with postmenopausal osteoporosis. International journal of clinical and experimental medicine 20 26629156
2003 CD100/Sema4D, a lymphocyte semaphorin involved in the regulation of humoral and cellular immune responses. Cytokine & growth factor reviews 20 12485616
2021 A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis. Science translational medicine 19 33627483
2015 CD8low CD100- T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection. Journal of virology 19 26378166
2022 SEMA4D/PlexinB1 promotes AML progression via activation of PI3K/Akt signaling. Journal of translational medicine 18 35794581
2019 CD100-plexin-B1 induces epithelial-mesenchymal transition of head and neck squamous cell carcinoma and promotes metastasis. Cancer letters 18 30981760
2019 SEMA4D under the posttranscriptional regulation of HuR and miR-4319 boosts cancer progression in esophageal squamous cell carcinoma. Cancer biology & therapy 18 31651222
2020 Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes. BioMed research international 17 32382577
2016 Sema4D is required in both the adaptive and innate immune responses of contact hypersensitivity. Molecular immunology 17 27614265
2007 A novel role for the semaphorin Sema4D in the induction of allo-responses. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 17 17950916
2022 Sema4D-plexin-B1 signaling in recruiting dental stem cells for vascular stabilization on a microfluidic platform. Lab on a chip 16 36331411
2019 LncRNA LINC01061 sponges miR-612 to regulate the oncogenic role of SEMA4D in cholangiocarcinoma. Biochemical and biophysical research communications 15 30967271
2013 Phage display identification of CD100 in human atherosclerotic plaque macrophages and foam cells. PloS one 15 24098722
2023 Inhibition of Sema4D attenuates pressure overload-induced pathological myocardial hypertrophy via the MAPK/NF-κB/NLRP3 pathways. Biochimica et biophysica acta. Molecular basis of disease 14 37952827
2023 Schistosome egg-derived extracellular vesicles deliver Sja-miR-71a inhibits host macrophage and neutrophil extracellular traps via targeting Sema4D. Cell communication and signaling : CCS 14 38129877
2021 SEMA4D Knockdown Attenuates β-Catenin-Dependent Tumor Progression in Colorectal Cancer. BioMed research international 13 34337054
2020 The emerging roles of semaphorin4D/CD100 in immunological diseases. Biochemical Society transactions 13 33258873
2012 Placental expression of CD100, CD72 and CD45 is dysregulated in human miscarriage. PloS one 13 22606231
2025 Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes. Nature communications 12 40121188
2021 CD100 modulates cytotoxicity of CD8+ T cells in patients with acute myocardial infarction. BMC immunology 12 33593275
2021 Soluble Sema4D in Plasma of Head and Neck Squamous Cell Carcinoma Patients Is Associated With Underlying Non-Inflamed Tumor Profile. Frontiers in immunology 12 33776991
2018 CD100 Effects in Macrophages and Its Roles in Atherosclerosis. Frontiers in cardiovascular medicine 11 30324109

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