{"gene":"SEMA3C","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2014,"finding":"GSCs preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate Rac1/NF-κB signaling in an autocrine/paracrine loop to promote GSC survival; introduction of activated Rac1 rescued the Sema3C knockdown phenotype in vivo, placing Rac1 downstream of Sema3C/PlexinA2/D1.","method":"Knockdown in orthotopic glioblastoma models, rescue with constitutively active Rac1, signaling assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with defined phenotype, in vivo rescue experiment with activated Rac1, multiple orthogonal methods across receptor identification and signaling readouts","pmids":["25464848"],"is_preprint":false},{"year":2015,"finding":"Transcription factor Bcl11a directly and negatively regulates Sema3C transcription; in Bcl11a-deficient neurons, elevated Sema3C expression impairs the multipolar-to-bipolar switch and radial migration of upper-layer cortical neurons; gain-of-function and rescue experiments confirmed Sema3C as a major downstream effector of Bcl11a in cortical migration.","method":"Conditional knockout mouse, in vivo gain-of-function and rescue experiments, ChIP/promoter binding assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct transcriptional regulation demonstrated by ChIP, multiple orthogonal in vivo rescue experiments","pmids":["26182416"],"is_preprint":false},{"year":2021,"finding":"MAOA activates SEMA3C transcription via Twist1; SEMA3C in turn stimulates cMET to facilitate prostate cancer perineural invasion via autocrine/paracrine signaling through co-activated PlexinA2 and NRP1 co-receptors.","method":"Knockdown/overexpression in prostate cancer cells, orthotopic xenograft model, in vitro perineural invasion assay, MAOA inhibitor treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling axis with multiple receptor components validated, single lab, in vivo corroboration","pmids":["33420365"],"is_preprint":false},{"year":2018,"finding":"SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate-ligand-independent manner via Plexin B1; Plexin B1 sema-domain:Fc fusion proteins suppress this RTK signaling and cell growth.","method":"RTK phosphorylation assays, PlexinB1 knockdown/inhibition, LNCaP xenograft castration model, Fc fusion protein treatment","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple RTKs validated, receptor-specific inhibitor (Fc fusion) used, in vivo xenograft corroboration, single lab but multiple orthogonal methods","pmids":["29348142"],"is_preprint":false},{"year":2015,"finding":"Neural crest-derived SEMA3C activates NRP1 in the outflow tract endothelium to promote endothelial-to-mesenchymal transition, supplying cells to endocardial cushions and repositioning cardiac neural crest cells, which are essential for OFT septal bridge formation.","method":"Ligand-specific and tissue-specific mouse mutants, explant assays, gene-expression studies, lineage tracing","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementary genetic mouse mutants plus explant functional assays and lineage tracing, multiple orthogonal approaches","pmids":["26053665"],"is_preprint":false},{"year":2017,"finding":"Foxc1/c2 directly activates Sema3C transcription in the cardiac outflow tract; Fgf8 (downstream of Tbx1 in the second heart field) inhibits Sema3C expression in cardiac neural crest cells via ERK1/2 activation; blocking FGF8 causes ectopic SEMA3C expression and migration defects of cNCCs.","method":"Transcription factor binding/reporter assays, Tbx1 hypomorph mouse, FGF8 blocking experiments in chick, ERK1/2 signaling assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional regulation and epistasis demonstrated, single lab, multiple genetic/pharmacological approaches","pmids":["28754980"],"is_preprint":false},{"year":2021,"finding":"FOXM1 binds to the promoter region of SEMA3C to elevate its expression; SEMA3C upregulates NRP2 and activates the Hedgehog signaling pathway; silencing SMO (Hedgehog transducer) negated the promoting effect of FOXM1 overexpression on M2 macrophage polarization.","method":"ChIP/promoter binding assay, siRNA knockdown, overexpression in macrophages, SMO inhibitor treatment","journal":"Diabetes research and clinical practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated, downstream pathway validated by SMO inhibitor rescue, single lab","pmids":["34742786"],"is_preprint":false},{"year":2019,"finding":"In corneal epithelial cells, SEMA3C signals through NRP2 (not NRP1) to promote epithelial wound closure and sensory nerve regeneration; siRNA knockdown of SEMA3C or NRP2-neutralizing antibodies decreased wound healing and nerve regeneration, whereas exogenous SEMA3C rescued these deficits in diabetic corneas.","method":"siRNA injection in vivo, neutralizing antibody treatment, exogenous recombinant SEMA3C injection, corneal wound healing and reinnervation readouts","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function in vivo with receptor-specific neutralization, single lab","pmids":["30679185"],"is_preprint":false},{"year":2018,"finding":"Post-crossing corpus callosum axons upregulate Ephrin-B1, which inhibits Sema3C/NRP1 signaling through direct interaction between Ephrin-B1 and Nrp1; this silencing is independent of Eph receptors and requires the N-glycosylation site N-139 in the extracellular domain of Ephrin-B1.","method":"In vivo mouse genetics, N-glycosylation site mutagenesis, co-immunoprecipitation, axon guidance assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — receptor interaction validated by Co-IP, functional consequence confirmed by site-directed mutagenesis (N139), in vivo axon navigation readout","pmids":["29779877"],"is_preprint":false},{"year":2012,"finding":"Motoneuronal Sema3C regulates the surface levels of shared Sema3 neuropilin receptors Nrp1 and Nrp2 in opposite directions at the growth cone, thereby setting population-specific axon sensitivity to limb-derived Sema3A, Sema3F, and Sema3C repellents and specifying stereotyped motor nerve trajectories.","method":"Targeted gain- and loss-of-function in chick neural tube (electroporation), in vivo analysis of spinal nerve positioning","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss-of-function with specific motor circuit readout, single lab","pmids":["22899844"],"is_preprint":false},{"year":2018,"finding":"The furin cleavage site 742RNRR745 in the basic domain of Sema3C is essential for its antiangiogenic activity; point mutation R745A abrogated the inhibitory effect of Sema3C on microcapillary formation by HUVECs in vitro.","method":"Site-directed mutagenesis of furin recognition site, in vitro angiogenesis (HUVEC tube formation) assay","journal":"Brazilian journal of medical and biological research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with functional in vitro readout, single lab, single method","pmids":["30304095"],"is_preprint":false},{"year":2016,"finding":"FR-Sema3C (a furin cleavage-resistant mutant) inhibits VEGF and PDGF-BB signal transduction in endothelial cells and suppresses choroidal neovascularization in a laser-induced CNV mouse model independently of VEGF binding.","method":"Intravitreal injection in mouse CNV model, FITC-dextran vascular imaging, RTK signaling assays in endothelial cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional assay with mutant protein, signaling assays in endothelial cells, single lab","pmids":["28036336"],"is_preprint":false},{"year":2023,"finding":"Sema3C directs β-catenin nuclear accumulation in a Rac1-dependent manner, leading to transactivation of Wnt target genes independently of Wnt ligand secretion; combined depletion of Sema3C and TCF1 extended survival in mouse glioblastoma model more than single-target inhibition.","method":"Wnt ligand secretion suppression, β-catenin nuclear fractionation, Rac1 inhibition, TCF1 co-depletion in orthotopic mouse GBM model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection with multiple orthogonal approaches (Rac1 dependence, Wnt-ligand independence, in vivo combination experiment), single lab but rigorous","pmids":["37080989"],"is_preprint":false},{"year":2024,"finding":"SEMA3C binds NRP1 and ITGB1 as functional receptors in both HCC cells and hepatic stellate cells (HSCs); in HCC cells this activates AKT/Gli1/c-Myc signaling to bolster self-renewal; in HSCs it activates NF-κB signaling, stimulating IL-6 release and HMGCR-dependent cholesterol synthesis; CAF-secreted TGF-β1 activates AP1 to augment SEMA3C expression in HCC cells, establishing a positive feedback loop.","method":"Co-immunoprecipitation/binding assays for NRP1/ITGB1, knockdown/overexpression, in vivo xenograft, pharmacological inhibition","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor binding identified, downstream pathways validated by pharmacological and genetic approaches, single lab","pmids":["38956074"],"is_preprint":false},{"year":2025,"finding":"CAF-secreted SEMA3C binds to NRP2 receptor on colorectal cancer liver metastasis-initiating cells, activating the MAPK pathway to promote liver metastasis.","method":"In vivo and in vitro experiments with SEMA3C-NRP2 receptor-ligand pair, MAPK pathway activation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-ligand interaction with downstream pathway validation in vivo and in vitro, single lab","pmids":["40402249"],"is_preprint":false},{"year":2024,"finding":"FOXA1 negatively regulates SEMA3C via intronic cis elements; mutations in the FOXA1 forkhead domain attenuate its inhibitory function in reporter assays, presumably by disrupting FOXA1 DNA binding, leading to elevated SEMA3C expression.","method":"Reporter assays, ChIP, analysis of prostate cancer specimens with FOXA1 mutations","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct intronic regulatory element function demonstrated by reporter assays with FOXA1 mutants, single lab","pmids":["38528115"],"is_preprint":false},{"year":2025,"finding":"KLF6 recruits the PCAF-p300/CBP complex to the SEMA3C promoter; together with FOSL2, this synergistically increases H3K23 succinylation and promotes SEMA3C transcription, which activates canonical Wnt-β-catenin signaling leading to upregulation of MYC and FOSL2 in 5-FU-resistant colon cancer cells.","method":"CUT&Tag, ATAC-seq, RNA-seq, chromatin immunoprecipitation (ChIP) for KLF6/FOSL2 binding, luciferase reporter assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates direct TF binding, epigenetic mark linked to SEMA3C transcription, downstream Wnt pathway activation validated, single lab","pmids":["40082673"],"is_preprint":false},{"year":2024,"finding":"P300 (EP300) increases H3K27 acetylation at the SEMA3C locus to promote its transcriptional activation in thyroid cancer; overexpressed SEMA3C enhances β-catenin nuclear translocation; DKK1 (Wnt inhibitor) offsets the pro-migratory and pro-stemness effects of SEMA3C overexpression.","method":"ChIP for H3K27ac, P300 overexpression, DKK1 pharmacological inhibition, β-catenin nuclear fractionation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic writer-target relationship and downstream β-catenin pathway validated, single lab","pmids":["39667698"],"is_preprint":false},{"year":2021,"finding":"SEMA3C overexpression in LNCaP cells upregulates Sonic Hedgehog (Shh) secretion, which in turn stimulates steroidogenic enzyme expression and androgen synthesis in prostatic stromal cells via the Shh pathway; blockade of Shh signaling with a smoothened antagonist abolished the effect. Notably, recombinant SEMA3C protein alone had no direct effect on steroidogenic activities in stromal cells.","method":"Conditioned media transfer, LC-MS steroid quantification, qPCR for steroidogenic enzymes, SMO antagonist treatment","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — indirect paracrine mechanism established by conditioned media experiments and Shh pathway blockade rescue, single lab","pmids":["33503318"],"is_preprint":false},{"year":2025,"finding":"SEMA3C inhibits cortical neuron dendrite outgrowth via PLXND1 and NRP2 receptors; genetic reduction of astrocyte-derived SEMA3C in RTT model mice enhances dendritic arborization, normalizes synaptic activity, and improves visual acuity and motor behavior.","method":"Astrocyte-neuron co-culture, PLXND1/NRP2 receptor blocking, conditional astrocyte-specific SEMA3C reduction in RTT mice, dendritic morphology, electrophysiology, behavioral assays","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identity validated by blocking experiments, in vivo conditional genetic approach with multiple functional readouts, preprint not yet peer-reviewed","pmids":["41279175"],"is_preprint":true}],"current_model":"SEMA3C is a secreted class-3 semaphorin that signals through receptor complexes including PlexinA2/D1, PlexinB1, NRP1, NRP2, and ITGB1 to activate downstream pathways (Rac1/NF-κB, MAPK, AKT, Wnt/β-catenin) in autocrine and paracrine manners; its transcription is directly regulated by multiple factors (Bcl11a, Foxc1/c2, FOXM1, FOXA1, KLF6/FOSL2/p300, P300-H3K27ac) and its bioactivity depends on furin-mediated processing of its basic domain; in development it guides axon navigation, cortical neuron migration, and cardiac outflow tract septation via NRP1-dependent endothelial-to-mesenchymal transition, while in cancer it drives tumor growth, treatment resistance, and metastasis through RTK transactivation (EGFR, ErbB2, MET) via PlexinB1 and Wnt pathway activation via Rac1-dependent β-catenin nuclear translocation."},"narrative":{"mechanistic_narrative":"SEMA3C is a secreted class-3 semaphorin that acts as an autocrine and paracrine ligand to guide neural development and to drive tumor growth, treatment resistance, and metastasis through neuropilin- and plexin-based receptor complexes [PMID:25464848, PMID:26053665, PMID:29348142]. In development, neural-crest- and motoneuron-derived SEMA3C patterns axon navigation and motor nerve trajectories by tuning NRP1/NRP2 surface levels and receptor sensitivity [PMID:22899844], guides upper-layer cortical neuron migration under negative transcriptional control by Bcl11a [PMID:26182416], and activates NRP1 in outflow-tract endothelium to promote endothelial-to-mesenchymal transition required for cardiac septation [PMID:26053665]. Its bioactivity depends on furin processing of the basic-domain cleavage site (742RNRR745), and a cleavage-resistant form acquires antiangiogenic activity that suppresses VEGF/PDGF-BB signaling [PMID:30304095, PMID:28036336]. In cancer, SEMA3C signals through PlexinA2/D1 to activate Rac1/NF-κB and through PlexinB1 to transactivate the RTKs EGFR, ErbB2, and MET in a cognate-ligand-independent manner [PMID:25464848, PMID:29348142]; it also drives Rac1-dependent β-catenin nuclear accumulation and ligand-independent Wnt target-gene transcription [PMID:37080989]. Receptor usage is context-specific, with NRP2 and ITGB1 engaged to activate Hedgehog, MAPK, AKT/Gli1/c-Myc, and NF-κB programs across distinct tumor and stromal cell types [PMID:38956074, PMID:40402249, PMID:34742786]. SEMA3C transcription is set by a dense network of regulators, repressed by Bcl11a and FOXA1 and activated by Foxc1/c2, FOXM1, MAOA-Twist1, and KLF6/FOSL2/p300-driven histone modification [PMID:26182416, PMID:38528115, PMID:28754980, PMID:34742786, PMID:33420365, PMID:40082673].","teleology":[{"year":2012,"claim":"Established that SEMA3C does not act as a simple repellent in isolation but tunes the cell's responsiveness to multiple Sema3 cues, answering how a single ligand specifies distinct motor axon trajectories.","evidence":"Gain- and loss-of-function by chick neural tube electroporation with in vivo spinal nerve positioning readouts","pmids":["22899844"],"confidence":"Medium","gaps":["Molecular mechanism by which SEMA3C oppositely regulates Nrp1 vs Nrp2 surface levels not defined","Downstream signaling not dissected"]},{"year":2014,"claim":"Defined the first SEMA3C cancer signaling axis, showing autocrine/paracrine ligand engages PlexinA2/D1 to drive Rac1/NF-κB-dependent survival, with Rac1 placed causally downstream by rescue.","evidence":"Knockdown in orthotopic glioblastoma models with constitutively active Rac1 rescue and signaling assays","pmids":["25464848"],"confidence":"High","gaps":["NF-κB target genes mediating survival not enumerated","Stoichiometry of PlexinA2/D1 receptor complex unresolved"]},{"year":2015,"claim":"Identified Bcl11a as a direct transcriptional repressor whose loss elevates SEMA3C to impair the multipolar-to-bipolar switch, linking SEMA3C dosage to cortical radial migration.","evidence":"Conditional knockout mouse with in vivo gain-of-function/rescue and ChIP promoter binding","pmids":["26182416"],"confidence":"High","gaps":["Receptor mediating SEMA3C effect on migrating neurons not identified","Signaling downstream of elevated SEMA3C in this context unknown"]},{"year":2015,"claim":"Showed neural-crest SEMA3C activates NRP1 in outflow-tract endothelium to drive endothelial-to-mesenchymal transition, explaining its essential role in cardiac septal bridge formation.","evidence":"Ligand- and tissue-specific mouse mutants, explant assays, and lineage tracing","pmids":["26053665"],"confidence":"High","gaps":["Plexin co-receptor for NRP1 in OFT endothelium not specified","Intracellular EndMT effectors not mapped"]},{"year":2017,"claim":"Placed SEMA3C in a cardiac transcriptional circuit, with Foxc1/c2 as direct activators and Fgf8/ERK1/2 as a repressive input that spatially restricts expression in migrating cardiac neural crest cells.","evidence":"TF binding/reporter assays, Tbx1 hypomorph mouse, and FGF8 blockade in chick with ERK1/2 readouts","pmids":["28754980"],"confidence":"Medium","gaps":["Direct vs indirect effect of ERK1/2 on the Sema3C promoter not resolved","Single-lab epistasis"]},{"year":2018,"claim":"Revealed that SEMA3C transactivates EGFR, ErbB2, and MET through PlexinB1 independently of their cognate ligands, defining a druggable mechanism of treatment-resistant tumor growth.","evidence":"RTK phosphorylation assays, PlexinB1 knockdown/inhibition, LNCaP castration xenograft, and PlexinB1 sema-domain:Fc fusion treatment","pmids":["29348142"],"confidence":"High","gaps":["Physical mode of PlexinB1-RTK coupling not structurally defined","Whether neuropilins participate in this complex unclear"]},{"year":2018,"claim":"Identified Ephrin-B1 as an Eph-receptor-independent silencer of SEMA3C/NRP1 signaling via direct N-glycosylation-dependent binding to NRP1, explaining loss of SEMA3C responsiveness in post-crossing callosal axons.","evidence":"Mouse genetics, N139 glycosylation-site mutagenesis, Co-IP, and axon guidance assays","pmids":["29779877"],"confidence":"High","gaps":["How Ephrin-B1 binding occludes SEMA3C engagement of NRP1 mechanistically unresolved","Generality to other Sema3/NRP1 pairs untested here"]},{"year":2018,"claim":"Demonstrated that furin cleavage of the basic-domain site 742RNRR745 is required for SEMA3C antiangiogenic activity, defining processing as a determinant of functional output.","evidence":"Site-directed mutagenesis (R745A) with HUVEC tube-formation assay","pmids":["30304095"],"confidence":"Medium","gaps":["Single in vitro readout","Receptor mediating antiangiogenic effect not identified"]},{"year":2016,"claim":"Showed a furin cleavage-resistant SEMA3C mutant inhibits VEGF and PDGF-BB signaling and suppresses neovascularization independently of VEGF binding, distinguishing processed from unprocessed forms functionally.","evidence":"Intravitreal FR-Sema3C injection in laser-induced CNV mouse, FITC-dextran imaging, endothelial RTK signaling assays","pmids":["28036336"],"confidence":"Medium","gaps":["Receptor mediating FR-Sema3C inhibition of VEGF/PDGF signaling not defined","Relationship to furin-dependent activity in #10 not reconciled"]},{"year":2021,"claim":"Connected upstream MAOA-Twist1 transcriptional activation of SEMA3C to cMET-driven perineural invasion via PlexinA2/NRP1 co-receptors, extending the signaling axis to prostate cancer dissemination.","evidence":"Knockdown/overexpression in prostate cancer cells, orthotopic xenograft, perineural invasion assay, MAOA inhibition","pmids":["33420365"],"confidence":"Medium","gaps":["Whether cMET activation here uses the PlexinB1 mechanism of #3 not addressed","Single lab"]},{"year":2021,"claim":"Identified FOXM1 as a direct promoter-binding activator of SEMA3C that engages NRP2 and Hedgehog signaling to drive M2 macrophage polarization, broadening SEMA3C to immune-stromal regulation.","evidence":"ChIP promoter binding, siRNA knockdown, macrophage overexpression, SMO inhibitor rescue","pmids":["34742786"],"confidence":"Medium","gaps":["Direct vs indirect link between SEMA3C/NRP2 and Hedgehog activation unresolved","Single lab"]},{"year":2021,"claim":"Showed SEMA3C acts indirectly via Shh secretion to stimulate stromal androgen synthesis, establishing a paracrine non-cell-autonomous mode distinct from direct stromal action.","evidence":"Conditioned media transfer, LC-MS steroid quantification, steroidogenic enzyme qPCR, SMO antagonist treatment","pmids":["33503318"],"confidence":"Medium","gaps":["Receptor on LNCaP cells transducing SEMA3C-driven Shh induction not identified","Recombinant SEMA3C alone inactive on stroma, mechanism of intermediary unclear"]},{"year":2023,"claim":"Established that SEMA3C drives ligand-independent Wnt signaling by Rac1-dependent β-catenin nuclear accumulation, and that combined SEMA3C/TCF1 targeting outperforms single-target therapy in glioblastoma.","evidence":"Wnt-ligand secretion suppression, β-catenin nuclear fractionation, Rac1 inhibition, TCF1 co-depletion in orthotopic GBM","pmids":["37080989"],"confidence":"High","gaps":["Receptor linking SEMA3C to Rac1 in this Wnt context not specified","How Rac1 promotes β-catenin nuclear import mechanistically open"]},{"year":2024,"claim":"Defined FOXA1 as a negative regulator of SEMA3C through intronic cis elements, with forkhead-domain mutations relieving repression, linking recurrent prostate cancer FOXA1 mutations to SEMA3C upregulation.","evidence":"Reporter assays with FOXA1 mutants, ChIP, and analysis of FOXA1-mutant prostate specimens","pmids":["38528115"],"confidence":"Medium","gaps":["Direct demonstration that mutants lose DNA binding inferred not shown","Single lab"]},{"year":2024,"claim":"Identified NRP1 and ITGB1 as functional SEMA3C receptors driving distinct programs in tumor versus stromal cells, with a TGF-β1/AP1 feedback loop reinforcing expression, depicting a self-sustaining tumor-microenvironment circuit.","evidence":"Co-IP/binding assays for NRP1/ITGB1, knockdown/overexpression, xenograft, pharmacological inhibition in HCC and hepatic stellate cells","pmids":["38956074"],"confidence":"Medium","gaps":["Plexin partner of NRP1/ITGB1 complex not defined","Single lab"]},{"year":2024,"claim":"Showed P300-driven H3K27 acetylation activates SEMA3C transcription to promote β-catenin nuclear translocation and stemness in thyroid cancer, adding an epigenetic activating input upstream of Wnt.","evidence":"H3K27ac ChIP, P300 overexpression, DKK1 inhibition, β-catenin nuclear fractionation","pmids":["39667698"],"confidence":"Medium","gaps":["Receptor transducing SEMA3C to β-catenin in thyroid cells not identified","Single lab"]},{"year":2025,"claim":"Showed CAF-secreted SEMA3C engages NRP2 to activate MAPK in colorectal liver metastasis-initiating cells, defining a stromal-to-tumor paracrine driver of organ-specific metastasis.","evidence":"In vivo and in vitro SEMA3C-NRP2 receptor-ligand experiments with MAPK activation readouts","pmids":["40402249"],"confidence":"Medium","gaps":["Plexin co-receptor with NRP2 not defined","Single lab"]},{"year":2025,"claim":"Established a chromatin mechanism in which KLF6 recruits PCAF-p300/CBP and cooperates with FOSL2 to deposit H3K23 succinylation activating SEMA3C and downstream Wnt, linking metabolic histone modification to 5-FU resistance.","evidence":"CUT&Tag, ATAC-seq, RNA-seq, ChIP for KLF6/FOSL2, luciferase reporters in 5-FU-resistant colon cancer","pmids":["40082673"],"confidence":"Medium","gaps":["Causality of H3K23 succinylation vs acetylation in SEMA3C activation not fully separated","Single lab"]},{"year":2025,"claim":"Implicated astrocyte-derived SEMA3C in restraining dendrite outgrowth via PLXND1 and NRP2, with its genetic reduction rescuing dendritic, synaptic, and behavioral deficits in a Rett syndrome model.","evidence":"Astrocyte-neuron co-culture, PLXND1/NRP2 blocking, conditional astrocyte SEMA3C reduction in RTT mice, electrophysiology and behavior (preprint)","pmids":["41279175"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Intracellular pathway downstream of PLXND1/NRP2 in dendrites not mapped"]},{"year":null,"claim":"How SEMA3C selects among its many receptor combinations (NRP1, NRP2, PlexinA2/D1, PlexinB1, PLXND1, ITGB1) to channel into distinct effector pathways in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of context-specific receptor complex assembly","Rules governing pathway choice (Rac1/NF-κB vs RTK vs Wnt vs MAPK vs Hedgehog) undefined","Role of furin processing in receptor selectivity not integrated across studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3,4,13,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4,7,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,12,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,13,16]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,8,9]}],"complexes":[],"partners":["NRP1","NRP2","PLXNA2","PLXND1","PLXNB1","ITGB1","EFNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99985","full_name":"Semaphorin-3C","aliases":["Semaphorin-E","Sema E"],"length_aa":751,"mass_kda":85.2,"function":"Binds to plexin family members and plays an important role in the regulation of developmental processes. Required for normal cardiovascular development during embryogenesis. Functions as attractant for growing axons, and thereby plays an important role in axon growth and axon guidance (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q99985/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMA3C","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEMA3C","total_profiled":1310},"omim":[{"mim_id":"621297","title":"LYMPHATIC ENDOTHELIAL TRANSCRIPTIONAL REGULATOR lncRNA 1; LETR1","url":"https://www.omim.org/entry/621297"},{"mim_id":"609297","title":"SEMAPHORIN 5A; SEMA5A","url":"https://www.omim.org/entry/609297"},{"mim_id":"606557","title":"BAF CHROMATIN REMODELING COMPLEX SUBUNIT BCL11A; BCL11A","url":"https://www.omim.org/entry/606557"},{"mim_id":"604282","title":"PLEXIN D1; PLXND1","url":"https://www.omim.org/entry/604282"},{"mim_id":"602645","title":"SEMAPHORIN 3C; SEMA3C","url":"https://www.omim.org/entry/602645"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEMA3C"},"hgnc":{"alias_symbol":["SemE"],"prev_symbol":["SEMAE"]},"alphafold":{"accession":"Q99985","domains":[{"cath_id":"-","chopping":"25-53_442-510","consensus_level":"medium","plddt":93.7821,"start":25,"end":510},{"cath_id":"-","chopping":"55-170","consensus_level":"medium","plddt":95.5703,"start":55,"end":170},{"cath_id":"2.130.10.10","chopping":"177-288_353-409","consensus_level":"medium","plddt":92.8979,"start":177,"end":409},{"cath_id":"3.30.1680.10","chopping":"513-571","consensus_level":"high","plddt":84.2456,"start":513,"end":571},{"cath_id":"2.60.40.10","chopping":"575-674","consensus_level":"high","plddt":87.2507,"start":575,"end":674}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99985","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99985-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99985-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMA3C","jax_strain_url":"https://www.jax.org/strain/search?query=SEMA3C"},"sequence":{"accession":"Q99985","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99985.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99985/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99985"}},"corpus_meta":[{"pmid":"25464848","id":"PMC_25464848","title":"Sema3C 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introduction of activated Rac1 rescued the Sema3C knockdown phenotype in vivo, placing Rac1 downstream of Sema3C/PlexinA2/D1.\",\n      \"method\": \"Knockdown in orthotopic glioblastoma models, rescue with constitutively active Rac1, signaling assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with defined phenotype, in vivo rescue experiment with activated Rac1, multiple orthogonal methods across receptor identification and signaling readouts\",\n      \"pmids\": [\"25464848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Transcription factor Bcl11a directly and negatively regulates Sema3C transcription; in Bcl11a-deficient neurons, elevated Sema3C expression impairs the multipolar-to-bipolar switch and radial migration of upper-layer cortical neurons; gain-of-function and rescue experiments confirmed Sema3C as a major downstream effector of Bcl11a in cortical migration.\",\n      \"method\": \"Conditional knockout mouse, in vivo gain-of-function and rescue experiments, ChIP/promoter binding assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct transcriptional regulation demonstrated by ChIP, multiple orthogonal in vivo rescue experiments\",\n      \"pmids\": [\"26182416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAOA activates SEMA3C transcription via Twist1; SEMA3C in turn stimulates cMET to facilitate prostate cancer perineural invasion via autocrine/paracrine signaling through co-activated PlexinA2 and NRP1 co-receptors.\",\n      \"method\": \"Knockdown/overexpression in prostate cancer cells, orthotopic xenograft model, in vitro perineural invasion assay, MAOA inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling axis with multiple receptor components validated, single lab, in vivo corroboration\",\n      \"pmids\": [\"33420365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate-ligand-independent manner via Plexin B1; Plexin B1 sema-domain:Fc fusion proteins suppress this RTK signaling and cell growth.\",\n      \"method\": \"RTK phosphorylation assays, PlexinB1 knockdown/inhibition, LNCaP xenograft castration model, Fc fusion protein treatment\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple RTKs validated, receptor-specific inhibitor (Fc fusion) used, in vivo xenograft corroboration, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29348142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Neural crest-derived SEMA3C activates NRP1 in the outflow tract endothelium to promote endothelial-to-mesenchymal transition, supplying cells to endocardial cushions and repositioning cardiac neural crest cells, which are essential for OFT septal bridge formation.\",\n      \"method\": \"Ligand-specific and tissue-specific mouse mutants, explant assays, gene-expression studies, lineage tracing\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementary genetic mouse mutants plus explant functional assays and lineage tracing, multiple orthogonal approaches\",\n      \"pmids\": [\"26053665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Foxc1/c2 directly activates Sema3C transcription in the cardiac outflow tract; Fgf8 (downstream of Tbx1 in the second heart field) inhibits Sema3C expression in cardiac neural crest cells via ERK1/2 activation; blocking FGF8 causes ectopic SEMA3C expression and migration defects of cNCCs.\",\n      \"method\": \"Transcription factor binding/reporter assays, Tbx1 hypomorph mouse, FGF8 blocking experiments in chick, ERK1/2 signaling assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional regulation and epistasis demonstrated, single lab, multiple genetic/pharmacological approaches\",\n      \"pmids\": [\"28754980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXM1 binds to the promoter region of SEMA3C to elevate its expression; SEMA3C upregulates NRP2 and activates the Hedgehog signaling pathway; silencing SMO (Hedgehog transducer) negated the promoting effect of FOXM1 overexpression on M2 macrophage polarization.\",\n      \"method\": \"ChIP/promoter binding assay, siRNA knockdown, overexpression in macrophages, SMO inhibitor treatment\",\n      \"journal\": \"Diabetes research and clinical practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated, downstream pathway validated by SMO inhibitor rescue, single lab\",\n      \"pmids\": [\"34742786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In corneal epithelial cells, SEMA3C signals through NRP2 (not NRP1) to promote epithelial wound closure and sensory nerve regeneration; siRNA knockdown of SEMA3C or NRP2-neutralizing antibodies decreased wound healing and nerve regeneration, whereas exogenous SEMA3C rescued these deficits in diabetic corneas.\",\n      \"method\": \"siRNA injection in vivo, neutralizing antibody treatment, exogenous recombinant SEMA3C injection, corneal wound healing and reinnervation readouts\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function in vivo with receptor-specific neutralization, single lab\",\n      \"pmids\": [\"30679185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Post-crossing corpus callosum axons upregulate Ephrin-B1, which inhibits Sema3C/NRP1 signaling through direct interaction between Ephrin-B1 and Nrp1; this silencing is independent of Eph receptors and requires the N-glycosylation site N-139 in the extracellular domain of Ephrin-B1.\",\n      \"method\": \"In vivo mouse genetics, N-glycosylation site mutagenesis, co-immunoprecipitation, axon guidance assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — receptor interaction validated by Co-IP, functional consequence confirmed by site-directed mutagenesis (N139), in vivo axon navigation readout\",\n      \"pmids\": [\"29779877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Motoneuronal Sema3C regulates the surface levels of shared Sema3 neuropilin receptors Nrp1 and Nrp2 in opposite directions at the growth cone, thereby setting population-specific axon sensitivity to limb-derived Sema3A, Sema3F, and Sema3C repellents and specifying stereotyped motor nerve trajectories.\",\n      \"method\": \"Targeted gain- and loss-of-function in chick neural tube (electroporation), in vivo analysis of spinal nerve positioning\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss-of-function with specific motor circuit readout, single lab\",\n      \"pmids\": [\"22899844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The furin cleavage site 742RNRR745 in the basic domain of Sema3C is essential for its antiangiogenic activity; point mutation R745A abrogated the inhibitory effect of Sema3C on microcapillary formation by HUVECs in vitro.\",\n      \"method\": \"Site-directed mutagenesis of furin recognition site, in vitro angiogenesis (HUVEC tube formation) assay\",\n      \"journal\": \"Brazilian journal of medical and biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with functional in vitro readout, single lab, single method\",\n      \"pmids\": [\"30304095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FR-Sema3C (a furin cleavage-resistant mutant) inhibits VEGF and PDGF-BB signal transduction in endothelial cells and suppresses choroidal neovascularization in a laser-induced CNV mouse model independently of VEGF binding.\",\n      \"method\": \"Intravitreal injection in mouse CNV model, FITC-dextran vascular imaging, RTK signaling assays in endothelial cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional assay with mutant protein, signaling assays in endothelial cells, single lab\",\n      \"pmids\": [\"28036336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sema3C directs β-catenin nuclear accumulation in a Rac1-dependent manner, leading to transactivation of Wnt target genes independently of Wnt ligand secretion; combined depletion of Sema3C and TCF1 extended survival in mouse glioblastoma model more than single-target inhibition.\",\n      \"method\": \"Wnt ligand secretion suppression, β-catenin nuclear fractionation, Rac1 inhibition, TCF1 co-depletion in orthotopic mouse GBM model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection with multiple orthogonal approaches (Rac1 dependence, Wnt-ligand independence, in vivo combination experiment), single lab but rigorous\",\n      \"pmids\": [\"37080989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEMA3C binds NRP1 and ITGB1 as functional receptors in both HCC cells and hepatic stellate cells (HSCs); in HCC cells this activates AKT/Gli1/c-Myc signaling to bolster self-renewal; in HSCs it activates NF-κB signaling, stimulating IL-6 release and HMGCR-dependent cholesterol synthesis; CAF-secreted TGF-β1 activates AP1 to augment SEMA3C expression in HCC cells, establishing a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation/binding assays for NRP1/ITGB1, knockdown/overexpression, in vivo xenograft, pharmacological inhibition\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor binding identified, downstream pathways validated by pharmacological and genetic approaches, single lab\",\n      \"pmids\": [\"38956074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAF-secreted SEMA3C binds to NRP2 receptor on colorectal cancer liver metastasis-initiating cells, activating the MAPK pathway to promote liver metastasis.\",\n      \"method\": \"In vivo and in vitro experiments with SEMA3C-NRP2 receptor-ligand pair, MAPK pathway activation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-ligand interaction with downstream pathway validation in vivo and in vitro, single lab\",\n      \"pmids\": [\"40402249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXA1 negatively regulates SEMA3C via intronic cis elements; mutations in the FOXA1 forkhead domain attenuate its inhibitory function in reporter assays, presumably by disrupting FOXA1 DNA binding, leading to elevated SEMA3C expression.\",\n      \"method\": \"Reporter assays, ChIP, analysis of prostate cancer specimens with FOXA1 mutations\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct intronic regulatory element function demonstrated by reporter assays with FOXA1 mutants, single lab\",\n      \"pmids\": [\"38528115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLF6 recruits the PCAF-p300/CBP complex to the SEMA3C promoter; together with FOSL2, this synergistically increases H3K23 succinylation and promotes SEMA3C transcription, which activates canonical Wnt-β-catenin signaling leading to upregulation of MYC and FOSL2 in 5-FU-resistant colon cancer cells.\",\n      \"method\": \"CUT&Tag, ATAC-seq, RNA-seq, chromatin immunoprecipitation (ChIP) for KLF6/FOSL2 binding, luciferase reporter assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates direct TF binding, epigenetic mark linked to SEMA3C transcription, downstream Wnt pathway activation validated, single lab\",\n      \"pmids\": [\"40082673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"P300 (EP300) increases H3K27 acetylation at the SEMA3C locus to promote its transcriptional activation in thyroid cancer; overexpressed SEMA3C enhances β-catenin nuclear translocation; DKK1 (Wnt inhibitor) offsets the pro-migratory and pro-stemness effects of SEMA3C overexpression.\",\n      \"method\": \"ChIP for H3K27ac, P300 overexpression, DKK1 pharmacological inhibition, β-catenin nuclear fractionation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic writer-target relationship and downstream β-catenin pathway validated, single lab\",\n      \"pmids\": [\"39667698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEMA3C overexpression in LNCaP cells upregulates Sonic Hedgehog (Shh) secretion, which in turn stimulates steroidogenic enzyme expression and androgen synthesis in prostatic stromal cells via the Shh pathway; blockade of Shh signaling with a smoothened antagonist abolished the effect. Notably, recombinant SEMA3C protein alone had no direct effect on steroidogenic activities in stromal cells.\",\n      \"method\": \"Conditioned media transfer, LC-MS steroid quantification, qPCR for steroidogenic enzymes, SMO antagonist treatment\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — indirect paracrine mechanism established by conditioned media experiments and Shh pathway blockade rescue, single lab\",\n      \"pmids\": [\"33503318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEMA3C inhibits cortical neuron dendrite outgrowth via PLXND1 and NRP2 receptors; genetic reduction of astrocyte-derived SEMA3C in RTT model mice enhances dendritic arborization, normalizes synaptic activity, and improves visual acuity and motor behavior.\",\n      \"method\": \"Astrocyte-neuron co-culture, PLXND1/NRP2 receptor blocking, conditional astrocyte-specific SEMA3C reduction in RTT mice, dendritic morphology, electrophysiology, behavioral assays\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identity validated by blocking experiments, in vivo conditional genetic approach with multiple functional readouts, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41279175\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEMA3C is a secreted class-3 semaphorin that signals through receptor complexes including PlexinA2/D1, PlexinB1, NRP1, NRP2, and ITGB1 to activate downstream pathways (Rac1/NF-κB, MAPK, AKT, Wnt/β-catenin) in autocrine and paracrine manners; its transcription is directly regulated by multiple factors (Bcl11a, Foxc1/c2, FOXM1, FOXA1, KLF6/FOSL2/p300, P300-H3K27ac) and its bioactivity depends on furin-mediated processing of its basic domain; in development it guides axon navigation, cortical neuron migration, and cardiac outflow tract septation via NRP1-dependent endothelial-to-mesenchymal transition, while in cancer it drives tumor growth, treatment resistance, and metastasis through RTK transactivation (EGFR, ErbB2, MET) via PlexinB1 and Wnt pathway activation via Rac1-dependent β-catenin nuclear translocation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMA3C is a secreted class-3 semaphorin that acts as an autocrine and paracrine ligand to guide neural development and to drive tumor growth, treatment resistance, and metastasis through neuropilin- and plexin-based receptor complexes [#0, #4, #3]. In development, neural-crest- and motoneuron-derived SEMA3C patterns axon navigation and motor nerve trajectories by tuning NRP1/NRP2 surface levels and receptor sensitivity [#9], guides upper-layer cortical neuron migration under negative transcriptional control by Bcl11a [#1], and activates NRP1 in outflow-tract endothelium to promote endothelial-to-mesenchymal transition required for cardiac septation [#4]. Its bioactivity depends on furin processing of the basic-domain cleavage site (742RNRR745), and a cleavage-resistant form acquires antiangiogenic activity that suppresses VEGF/PDGF-BB signaling [#10, #11]. In cancer, SEMA3C signals through PlexinA2/D1 to activate Rac1/NF-\\u03baB and through PlexinB1 to transactivate the RTKs EGFR, ErbB2, and MET in a cognate-ligand-independent manner [#0, #3]; it also drives Rac1-dependent \\u03b2-catenin nuclear accumulation and ligand-independent Wnt target-gene transcription [#12]. Receptor usage is context-specific, with NRP2 and ITGB1 engaged to activate Hedgehog, MAPK, AKT/Gli1/c-Myc, and NF-\\u03baB programs across distinct tumor and stromal cell types [#13, #14, #6]. SEMA3C transcription is set by a dense network of regulators, repressed by Bcl11a and FOXA1 and activated by Foxc1/c2, FOXM1, MAOA-Twist1, and KLF6/FOSL2/p300-driven histone modification [#1, #15, #5, #6, #2, #16].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that SEMA3C does not act as a simple repellent in isolation but tunes the cell's responsiveness to multiple Sema3 cues, answering how a single ligand specifies distinct motor axon trajectories.\",\n      \"evidence\": \"Gain- and loss-of-function by chick neural tube electroporation with in vivo spinal nerve positioning readouts\",\n      \"pmids\": [\"22899844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which SEMA3C oppositely regulates Nrp1 vs Nrp2 surface levels not defined\", \"Downstream signaling not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the first SEMA3C cancer signaling axis, showing autocrine/paracrine ligand engages PlexinA2/D1 to drive Rac1/NF-\\u03baB-dependent survival, with Rac1 placed causally downstream by rescue.\",\n      \"evidence\": \"Knockdown in orthotopic glioblastoma models with constitutively active Rac1 rescue and signaling assays\",\n      \"pmids\": [\"25464848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NF-\\u03baB target genes mediating survival not enumerated\", \"Stoichiometry of PlexinA2/D1 receptor complex unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified Bcl11a as a direct transcriptional repressor whose loss elevates SEMA3C to impair the multipolar-to-bipolar switch, linking SEMA3C dosage to cortical radial migration.\",\n      \"evidence\": \"Conditional knockout mouse with in vivo gain-of-function/rescue and ChIP promoter binding\",\n      \"pmids\": [\"26182416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating SEMA3C effect on migrating neurons not identified\", \"Signaling downstream of elevated SEMA3C in this context unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed neural-crest SEMA3C activates NRP1 in outflow-tract endothelium to drive endothelial-to-mesenchymal transition, explaining its essential role in cardiac septal bridge formation.\",\n      \"evidence\": \"Ligand- and tissue-specific mouse mutants, explant assays, and lineage tracing\",\n      \"pmids\": [\"26053665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plexin co-receptor for NRP1 in OFT endothelium not specified\", \"Intracellular EndMT effectors not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed SEMA3C in a cardiac transcriptional circuit, with Foxc1/c2 as direct activators and Fgf8/ERK1/2 as a repressive input that spatially restricts expression in migrating cardiac neural crest cells.\",\n      \"evidence\": \"TF binding/reporter assays, Tbx1 hypomorph mouse, and FGF8 blockade in chick with ERK1/2 readouts\",\n      \"pmids\": [\"28754980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect of ERK1/2 on the Sema3C promoter not resolved\", \"Single-lab epistasis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed that SEMA3C transactivates EGFR, ErbB2, and MET through PlexinB1 independently of their cognate ligands, defining a druggable mechanism of treatment-resistant tumor growth.\",\n      \"evidence\": \"RTK phosphorylation assays, PlexinB1 knockdown/inhibition, LNCaP castration xenograft, and PlexinB1 sema-domain:Fc fusion treatment\",\n      \"pmids\": [\"29348142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical mode of PlexinB1-RTK coupling not structurally defined\", \"Whether neuropilins participate in this complex unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified Ephrin-B1 as an Eph-receptor-independent silencer of SEMA3C/NRP1 signaling via direct N-glycosylation-dependent binding to NRP1, explaining loss of SEMA3C responsiveness in post-crossing callosal axons.\",\n      \"evidence\": \"Mouse genetics, N139 glycosylation-site mutagenesis, Co-IP, and axon guidance assays\",\n      \"pmids\": [\"29779877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ephrin-B1 binding occludes SEMA3C engagement of NRP1 mechanistically unresolved\", \"Generality to other Sema3/NRP1 pairs untested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that furin cleavage of the basic-domain site 742RNRR745 is required for SEMA3C antiangiogenic activity, defining processing as a determinant of functional output.\",\n      \"evidence\": \"Site-directed mutagenesis (R745A) with HUVEC tube-formation assay\",\n      \"pmids\": [\"30304095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro readout\", \"Receptor mediating antiangiogenic effect not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed a furin cleavage-resistant SEMA3C mutant inhibits VEGF and PDGF-BB signaling and suppresses neovascularization independently of VEGF binding, distinguishing processed from unprocessed forms functionally.\",\n      \"evidence\": \"Intravitreal FR-Sema3C injection in laser-induced CNV mouse, FITC-dextran imaging, endothelial RTK signaling assays\",\n      \"pmids\": [\"28036336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating FR-Sema3C inhibition of VEGF/PDGF signaling not defined\", \"Relationship to furin-dependent activity in #10 not reconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected upstream MAOA-Twist1 transcriptional activation of SEMA3C to cMET-driven perineural invasion via PlexinA2/NRP1 co-receptors, extending the signaling axis to prostate cancer dissemination.\",\n      \"evidence\": \"Knockdown/overexpression in prostate cancer cells, orthotopic xenograft, perineural invasion assay, MAOA inhibition\",\n      \"pmids\": [\"33420365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cMET activation here uses the PlexinB1 mechanism of #3 not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified FOXM1 as a direct promoter-binding activator of SEMA3C that engages NRP2 and Hedgehog signaling to drive M2 macrophage polarization, broadening SEMA3C to immune-stromal regulation.\",\n      \"evidence\": \"ChIP promoter binding, siRNA knockdown, macrophage overexpression, SMO inhibitor rescue\",\n      \"pmids\": [\"34742786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect link between SEMA3C/NRP2 and Hedgehog activation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed SEMA3C acts indirectly via Shh secretion to stimulate stromal androgen synthesis, establishing a paracrine non-cell-autonomous mode distinct from direct stromal action.\",\n      \"evidence\": \"Conditioned media transfer, LC-MS steroid quantification, steroidogenic enzyme qPCR, SMO antagonist treatment\",\n      \"pmids\": [\"33503318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on LNCaP cells transducing SEMA3C-driven Shh induction not identified\", \"Recombinant SEMA3C alone inactive on stroma, mechanism of intermediary unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that SEMA3C drives ligand-independent Wnt signaling by Rac1-dependent \\u03b2-catenin nuclear accumulation, and that combined SEMA3C/TCF1 targeting outperforms single-target therapy in glioblastoma.\",\n      \"evidence\": \"Wnt-ligand secretion suppression, \\u03b2-catenin nuclear fractionation, Rac1 inhibition, TCF1 co-depletion in orthotopic GBM\",\n      \"pmids\": [\"37080989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor linking SEMA3C to Rac1 in this Wnt context not specified\", \"How Rac1 promotes \\u03b2-catenin nuclear import mechanistically open\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined FOXA1 as a negative regulator of SEMA3C through intronic cis elements, with forkhead-domain mutations relieving repression, linking recurrent prostate cancer FOXA1 mutations to SEMA3C upregulation.\",\n      \"evidence\": \"Reporter assays with FOXA1 mutants, ChIP, and analysis of FOXA1-mutant prostate specimens\",\n      \"pmids\": [\"38528115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that mutants lose DNA binding inferred not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified NRP1 and ITGB1 as functional SEMA3C receptors driving distinct programs in tumor versus stromal cells, with a TGF-\\u03b21/AP1 feedback loop reinforcing expression, depicting a self-sustaining tumor-microenvironment circuit.\",\n      \"evidence\": \"Co-IP/binding assays for NRP1/ITGB1, knockdown/overexpression, xenograft, pharmacological inhibition in HCC and hepatic stellate cells\",\n      \"pmids\": [\"38956074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Plexin partner of NRP1/ITGB1 complex not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed P300-driven H3K27 acetylation activates SEMA3C transcription to promote \\u03b2-catenin nuclear translocation and stemness in thyroid cancer, adding an epigenetic activating input upstream of Wnt.\",\n      \"evidence\": \"H3K27ac ChIP, P300 overexpression, DKK1 inhibition, \\u03b2-catenin nuclear fractionation\",\n      \"pmids\": [\"39667698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor transducing SEMA3C to \\u03b2-catenin in thyroid cells not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed CAF-secreted SEMA3C engages NRP2 to activate MAPK in colorectal liver metastasis-initiating cells, defining a stromal-to-tumor paracrine driver of organ-specific metastasis.\",\n      \"evidence\": \"In vivo and in vitro SEMA3C-NRP2 receptor-ligand experiments with MAPK activation readouts\",\n      \"pmids\": [\"40402249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Plexin co-receptor with NRP2 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a chromatin mechanism in which KLF6 recruits PCAF-p300/CBP and cooperates with FOSL2 to deposit H3K23 succinylation activating SEMA3C and downstream Wnt, linking metabolic histone modification to 5-FU resistance.\",\n      \"evidence\": \"CUT&Tag, ATAC-seq, RNA-seq, ChIP for KLF6/FOSL2, luciferase reporters in 5-FU-resistant colon cancer\",\n      \"pmids\": [\"40082673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of H3K23 succinylation vs acetylation in SEMA3C activation not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated astrocyte-derived SEMA3C in restraining dendrite outgrowth via PLXND1 and NRP2, with its genetic reduction rescuing dendritic, synaptic, and behavioral deficits in a Rett syndrome model.\",\n      \"evidence\": \"Astrocyte-neuron co-culture, PLXND1/NRP2 blocking, conditional astrocyte SEMA3C reduction in RTT mice, electrophysiology and behavior (preprint)\",\n      \"pmids\": [\"41279175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Intracellular pathway downstream of PLXND1/NRP2 in dendrites not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEMA3C selects among its many receptor combinations (NRP1, NRP2, PlexinA2/D1, PlexinB1, PLXND1, ITGB1) to channel into distinct effector pathways in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of context-specific receptor complex assembly\", \"Rules governing pathway choice (Rac1/NF-\\u03baB vs RTK vs Wnt vs MAPK vs Hedgehog) undefined\", \"Role of furin processing in receptor selectivity not integrated across studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3, 4, 13, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 7, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 12, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 13, 16]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NRP1\", \"NRP2\", \"PLXNA2\", \"PLXND1\", \"PLXNB1\", \"ITGB1\", \"EFNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}