Affinage

SEMA6D

Semaphorin-6D · UniProt Q8NFY4

Length
1073 aa
Mass
119.9 kDa
Annotated
2026-04-28
18 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SEMA6D is a transmembrane class 6 semaphorin that functions as both a ligand and a receptor, enabling bidirectional signaling that regulates cell migration, proliferation, and immune cell function across cardiac development, tumor immunity, and neurodegeneration. As a ligand, SEMA6D binds Plexin-A1 — forming context-dependent co-receptor complexes with VEGFR2 or Off-track to promote or inhibit migration, respectively — and also signals through Plexin-A4 to suppress CD8+ T cell infiltration and anti-tumor immunity, while engaging TREM2 on microglia to stimulate Aβ plaque phagocytosis (PMID:14977921, PMID:38329122, PMID:40737431). As a receptor (reverse signaling), Plexin-A1 binding to SEMA6D recruits Abl kinase to its cytoplasmic tail, phosphorylating Enabled to drive myocardial cell migration, and SEMA6D also activates Rho GTPase through a PLXNA1–FARP1 axis to promote atrioventricular cushion mesenchymal cell formation (PMID:15543137, PMID:28172500). In cardiomyocytes, SEMA6D maintains perinatal proliferative capacity by sustaining MYCN expression, and its deletion causes myocardial hypoplasia and premature maturation (PMID:31042497).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2004 High

    Establishing that SEMA6D acts as a ligand for Plexin-A1 and that the biological outcome (pro- vs. anti-migratory) depends on the co-receptor complex formed (VEGFR2 vs. Off-track), revealing how a single semaphorin can generate opposite cellular responses in adjacent cardiac regions.

    Evidence Co-immunoprecipitation of receptor complexes, cardiac explant migration assays, RNA interference in chick embryos

    PMID:14977921

    Open questions at the time
    • Co-receptor switching mechanism between VEGFR2 and Off-track complexes is not defined
    • Whether other co-receptors participate in additional tissue contexts is unknown
  2. 2004 High

    Demonstrating that SEMA6D also functions as a receptor (reverse signaling): Plexin-A1 binding recruits Abl kinase to the SEMA6D cytoplasmic tail, phosphorylates Enabled, and promotes myocardial trabeculation — establishing the bidirectional signaling paradigm for class 6 semaphorins.

    Evidence Co-immunoprecipitation of Abl with SEMA6D cytoplasmic tail, phosphorylation assays, constitutive activation/inhibition constructs with migration readouts in chick embryos

    PMID:15543137

    Open questions at the time
    • Structural basis of Abl recruitment to SEMA6D cytoplasmic domain is unresolved
    • Whether reverse signaling operates outside cardiac development is untested
  3. 2016 High

    Placing SEMA6D downstream of BMP signaling and upstream of Rho GTPase activation via PLXNA1–FARP1, defining the forward signaling cascade that drives atrioventricular cushion mesenchymal cell formation and migration.

    Evidence Conditional Sema6D knockout in endocardial cells (Nfatc1-Cre), ex vivo explant culture, Rho activation assays

    PMID:28172500

    Open questions at the time
    • How FARP1 is recruited to the Plexin-A1 complex is mechanistically unclear
    • Whether this axis contributes to human congenital heart defects is unknown
  4. 2019 High

    Revealing a cardiomyocyte-autonomous role for SEMA6D in maintaining perinatal proliferative and immature state through MYCN, showing that loss of SEMA6D causes myocardial hypoplasia and premature sarcomeric maturation.

    Evidence Cardiomyocyte-specific conditional gene deletion, echocardiography, gene expression analysis in mice

    PMID:31042497

    Open questions at the time
    • Direct mechanism linking SEMA6D to MYCN transcriptional regulation is not established
    • Whether this pathway is relevant to cardiac regeneration strategies is untested
  5. 2022 High

    Determining the structural basis for SEMA6D–Plexin-A1 binding selectivity: crystal structure shows Van der Waals shape complementarity at interface hotspots rather than specific polar contacts drives preference for Plexin-A1 over other class A plexins.

    Evidence Crystal structure of SEMA6D–Plexin-A1 complex, alanine scanning mutagenesis, molecular dynamics simulations

    PMID:36156831

    Open questions at the time
    • Structure of SEMA6D bound to Plexin-A4 or TREM2 is unavailable for comparison
    • No full-length SEMA6D structure including the cytoplasmic signaling domain exists
  6. 2024 High

    Extending SEMA6D's ligand function to anti-tumor immunity: SEMA6D expressed by non-hematopoietic cells signals through Plexin-A4 to impair CD8+ T cell infiltration and activation, and Sema6d knockout restores anti-tumor immunity and PD-1 blockade efficacy.

    Evidence Sema6d knockout mice, tumor implantation, flow cytometry, PD-1 blockade experiments

    PMID:38329122

    Open questions at the time
    • Plexin-A4 downstream signaling in T cells is not defined
    • Whether SEMA6D immunosuppression generalizes across tumor types is unclear
  7. 2025 High

    Identifying TREM2 as a novel SEMA6D receptor on microglia: neuronal SEMA6D colocalizes with Aβ plaques and activates microglial phagocytosis in a TREM2-dependent manner, linking SEMA6D to Alzheimer's disease neuroinflammation.

    Evidence TREM2 knockout iPSC-derived microglia stimulated with SEMA6D, phagocytosis assays, spatial transcriptomics and immunostaining of human brain tissue

    PMID:40737431

    Open questions at the time
    • Binding interface between SEMA6D and TREM2 is structurally uncharacterized
    • Whether SEMA6D–TREM2 interaction extends to other neurodegenerative contexts is unknown
    • Signaling cascade downstream of TREM2 engagement by SEMA6D is not delineated
  8. 2022 Medium

    Demonstrating a chondroprotective role for SEMA6D: overexpression suppresses p38 MAPK activation and promotes anabolic over catabolic gene programs in chondrocytes, later linked to suppression of the tissue renin-angiotensin system (AGT/AGTR1a/IL-1β axis).

    Evidence Luciferase reporter assay for miR-7 targeting, SEMA6D overexpression in chondrocytes, p38 phosphorylation assays, AAV5-based overexpression in rat OA model with RNA-seq

    PMID:35757507 PMID:40184436

    Open questions at the time
    • Receptor mediating SEMA6D signaling in chondrocytes is unidentified
    • Single-lab findings await independent replication
    • Mechanism connecting SEMA6D to p38 MAPK and tRAS suppression is not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full receptor repertoire of SEMA6D (beyond Plexin-A1, Plexin-A4, and TREM2) remains undefined, as does the structural basis of its cytoplasmic domain's ability to recruit distinct signaling effectors for reverse signaling in different tissue contexts.
  • No structure of full-length SEMA6D including cytoplasmic domain
  • Reverse signaling outside cardiac tissue is undemonstrated
  • Therapeutic potential of blocking SEMA6D in tumors or activating it for neurodegeneration is untested in clinical models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 2
Partners
ABL1ENAHFARP1KDRPLXNA1PLXNA4TREM2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Sema6D binds Plexin-A1 as its major receptor, and Plexin-A1 forms distinct receptor complexes depending on region: with VEGFR2 (KDR) in the conotruncal segment to promote cell migration, and with Off-track in the ventricle to inhibit cell migration, enabling Sema6D to exert opposite biological activities in adjacent cardiac regions. Ectopic expression, RNA interference in chick embryos, cardiac explant migration assays, co-immunoprecipitation of receptor complexes Genes & development High 14977921
2004 Sema6D functions as both a ligand and a receptor (reverse signaling) for Plexin-A1 in myocardial cells. Upon ligation by Plexin-A1, Abl kinase is recruited to the cytoplasmic tail of Sema6D and activated, resulting in phosphorylation of Enabled (Ena) and its dissociation from Sema6D, promoting myocardial cell migration into trabeculae. Knockdown of Sema6D and Plexin-A1 in chick embryos, expression of Plexin-A1 extracellular domain rescue experiments, co-immunoprecipitation of Abl with Sema6D cytoplasmic tail, phosphorylation assays, constitutive activation/inhibition constructs with cell migration readouts Nature cell biology High 15543137
2016 Sema6D is a transcriptional target downstream of BMP signaling in AV cushion mesenchymal cells, and SEMA6D activates Rho GTPase through a PLXNA1-FARP1 signaling axis to promote cushion mesenchymal cell formation and migration. Microarray analysis of BMP-stimulated AV cushion cell line (tsA58-AVM), conditional Sema6D knockout in endocardial cells (Nfatc1-Cre), ex vivo explant culture, in vivo transgenic studies, Rho activation assays Cardiovascular research High 28172500
2019 SEMA6D is required in cardiomyocytes to maintain a proliferative and immature state during the perinatal period; cardiomyocyte-specific deletion of Sema6D reduces expression of MYCN and downstream cell cycle regulators, leading to hypoplastic myocardial walls and accelerated sarcomeric protein maturation. Conditional gene deletion in cardiomyocytes, histology, gene expression analysis, echocardiography Developmental biology High 31042497
2017 SEMA6D functions downstream of miR-27b in endothelial cells to regulate pericyte recruitment; miR-27b represses SEMA6D expression, and silencing of SEMA6D rescues reduced pericyte adhesion caused by miR-27a/b inhibition, while inhibition of SEMA6D increases endothelial-pericyte barrier function. miR-27b overexpression/inhibition in endothelial cells, siRNA silencing of SEMA6D, in vitro pericyte adhesion and barrier function assays, in vivo locked nucleic acid inhibition Cardiovascular research Medium 28453731
2022 Crystal structure of the Sema6D–Plexin-A1 complex reveals that binding selectivity of Sema6D for Plexin-A1 over other class A plexins is determined primarily by shape complementarity (Van der Waals interactions) at hotspot residues in the binding interface rather than by specific polar interactions. Crystallographic structure determination of Sema6D–Plexin-A1 complex, biophysical binding analysis, in silico alanine scanning, molecular dynamics simulations of mutants Protein science High 36156831
2024 Sema6D forward signaling through its receptor Plexin-A4 impairs CD8+ T cell infiltration and activation/proliferation in murine oral tumors; Sema6D expressed by non-hematopoietic cells is responsible for this immunosuppressive phenotype, and Sema6d knockout restores anti-tumor T cell responses and PD-1 blockade efficacy. Sema6d knockout mice, tumor implantation, flow cytometry of tumor-infiltrating lymphocytes, Plexin-A4 identified as receptor by cell-based assays, PD-1 blockade treatment experiments JCI insight High 38329122
2025 Neuronal SEMA6D interacts with TREM2 on microglia to regulate microglial activation and Aβ plaque phagocytosis; SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia in human brain, and SEMA6D induces microglial activation and phagocytosis in a TREM2-dependent manner. Single-nucleus transcriptomics network analysis, spatial transcriptomics, tissue immunostaining of human brains, TREM2 knockout iPSC-derived microglia with SEMA6D stimulation and phagocytosis assays Science translational medicine High 40737431
2022 SEMA6D is a direct target of miR-7, which negatively regulates its expression; SEMA6D promotes anabolic and suppresses catabolic activities in C28/I2 chondrocytes by inhibiting activation of the p38 MAPK signaling pathway. miR-7 mimic/inhibitor transfection, luciferase reporter assay confirming direct miR-7 targeting of SEMA6D 3'UTR, SEMA6D overexpression in chondrocytes, p38 phosphorylation assays, rat OA model with histology Oxidative medicine and cellular longevity Medium 35757507
2025 SEMA6D overexpression in chondrocytes suppresses the AGT/AGTR1a/IL-1β axis of the tissue-localized renin-angiotensin system (tRAS), enhancing extracellular matrix homeostasis (increased Aggrecan, COL2A1; decreased MMP13, COL10A1, Runx2) and reducing cartilage degradation in an OA rat model. Gene transfection of chondrocytes, RNA sequencing, biochemical pathway analysis, AAV5-based SEMA6D overexpression in rat OA model, radiological and histological analyses FASEB journal Medium 40184436
2021 SEMA6D is a direct target of miR-195 in breast cancer cells; reduced SEMA6D expression caused by miR-195-driven repression is associated with chemoresistance, confirmed by miRNA mimic pull-down RNA sequencing and functional chemosensitivity assays. RNA-sequencing of miR-195 mimic pull-downs from breast cancer cell lines, siRNA knockdown of SEMA6D, MTT and colony forming survival assays Cancers Medium 34885090
2022 SEMA6D overexpression has cell-type-specific effects on proliferation, migration, and invasion of breast cell lines, and alters expression of EMT-related and Notch signaling pathway genes. SEMA6D overexpression in MCF10A, MCF7, and MDA-MB-231 cells; proliferation, migration, invasion, and anchorage-independent growth assays; gene expression analysis ACS omega Low 35571788

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes & development 242 14977921
2004 Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nature cell biology 181 15543137
2017 Shear stress-regulated miR-27b controls pericyte recruitment by repressing SEMA6A and SEMA6D. Cardiovascular research 36 28453731
2015 SEMA6D Expression and Patient Survival in Breast Invasive Carcinoma. International journal of breast cancer 36 25973277
2020 CircUBAP2 promotes SEMA6D expression to enhance the cisplatin resistance in osteosarcoma through sponging miR-506-3p by activating Wnt/β-catenin signaling pathway. Journal of molecular histology 35 32472335
2021 MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer. Cancers 31 34885090
2016 Sema6D acts downstream of bone morphogenetic protein signalling to promote atrioventricular cushion development in mice. Cardiovascular research 22 28172500
2013 Sema6B, Sema6C, and Sema6D expression and function during mammalian retinal development. PloS one 19 23646199
2020 Correction to: CircUBAP2 promotes SEMA6D expression to enhance the cisplatin resistance in osteosarcoma through sponging miR-506-3p by activating Wnt/β-catenin signaling pathway. Journal of molecular histology 16 32666371
2019 SEMA6D regulates perinatal cardiomyocyte proliferation and maturation in mice. Developmental biology 12 31042497
2024 Sema6D forward signaling impairs T cell activation and proliferation in head and neck cancer. JCI insight 10 38329122
2022 SEMA6D Differentially Regulates Proliferation, Migration, and Invasion of Breast Cell Lines. ACS omega 10 35571788
2022 SEMA6D, Negatively Regulated by miR-7, Contributes to C28/I2 chondrocyte's Catabolic and Anabolic Activities via p38 Signaling Pathway. Oxidative medicine and cellular longevity 9 35757507
2021 Neuroimaging genetic associations between SEMA6D, brain structure, and reading skills. Journal of clinical and experimental neuropsychology 9 33960276
2022 Hybrid in vitro/in silico analysis of low-affinity protein-protein interactions that regulate signal transduction by Sema6D. Protein science : a publication of the Protein Society 7 36156831
2025 Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer's disease. Science translational medicine 5 40737431
2025 SEMA6D modulates extracellular matrix metabolism in osteoarthritis by inhibiting the AGT/AGTR1a/IL-1β axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 40184436
2024 The Role of Semaphorin 6D (Sema6D) in Non-Muscle-Invasive Bladder Cancer-A Preliminary Study on Human Plasma and Urine. Biomedicines 2 39061999