{"gene":"SEMA4C","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2000,"finding":"Sema4C interacts with PSD-95 family members (PSD-95/SAP90, PSD-93/chapsin110, SAP97/DLG-1) via their PDZ domains; Sema4C is enriched in the synaptic vesicle fraction and Triton X-100-insoluble post-synaptic density fraction of mouse neocortex, and colocalizes with PSD-95 in cortical neurons with a dot-like pattern along neurites.","method":"Co-immunoprecipitation, subcellular fractionation, immunostaining, colocalization in neocortical culture","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and fractionation in a single lab, two orthogonal methods (biochemical fractionation + immunostaining)","pmids":["11134026"],"is_preprint":false},{"year":2005,"finding":"Sema4C is required for myogenic differentiation: depletion of Sema4C in C2C12 myoblasts markedly attenuated myotube formation, and both the extracellular Sema domain fusion protein and a peptide corresponding to the intracellular C-terminal region each inhibited C2C12 differentiation, indicating that Sema4C-mediated cell–cell interaction is necessary for terminal myogenic differentiation.","method":"siRNA knockdown of Sema4C in C2C12 cells, dominant-negative peptide/fusion protein inhibition, in vivo muscle regeneration model","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotypic readout plus domain-based mechanistic dissection, single lab","pmids":["15811348"],"is_preprint":false},{"year":2007,"finding":"Sema4C promotes terminal myogenic differentiation via the p38 MAPK pathway: overexpression of Sema4C in C2C12 cells directly elicited p38 phosphorylation and accelerated myotube formation; these effects were abolished by the p38α-specific inhibitor SB203580. Knockdown of Sema4C suppressed p38 phosphorylation and dramatically reduced myotube formation. Sema4C activated the myogenin promoter in a p38-dependent manner.","method":"Stable and transient Sema4C overexpression, siRNA knockdown, pharmacological p38 inhibition (SB203580), Western blotting, myogenin promoter reporter assay, in vivo muscle regeneration model","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (OE, KD, inhibitor, reporter assay) in a single rigorous study, replicated across in vitro and in vivo contexts","pmids":["17498836"],"is_preprint":false},{"year":2010,"finding":"Sema4C plays an important role in TGF-β1-induced epithelial-mesenchymal transition (EMT) in renal proximal tubular epithelial cells through activation of p38 MAPK: TGF-β1 upregulates Sema4C, Sema4C knockdown inhibits p38 phosphorylation and reverses EMT, and Sema4C overexpression elicits p38 phosphorylation and promotes EMT; these effects are blocked by the p38 inhibitor SB203580.","method":"siRNA knockdown, plasmid overexpression, SB203580 p38 inhibitor, Western blotting, immunohistochemistry, ELISA, in vivo 5/6 nephrectomy rat model","journal":"Nephrology, dialysis, transplantation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, OE, pharmacological inhibition, in vivo model) in a single study, consistent results across all arms","pmids":["20959347"],"is_preprint":false},{"year":2010,"finding":"Sema4C-Plexin B2 signaling regulates ureteric branching during kidney development: Sema4C (ligand for Plexin B2) stimulates ureteric epithelial branching in wild-type kidney explants but not in Plxnb2−/− explants; Plexin B2 co-immunoprecipitates with the Ret receptor tyrosine kinase in embryonic kidneys, suggesting modulation of GDNF/Ret signaling.","method":"Genetic knockout (Plxnb2−/−), kidney explant branching assay, co-immunoprecipitation (Plexin B2–Ret interaction), histological analysis","journal":"Differentiation; research in biological diversity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (KO rescue), ex vivo functional assay, and biochemical interaction (Co-IP) in same study","pmids":["21035938"],"is_preprint":false},{"year":2013,"finding":"Erbin directly interacts with Sema4C in HK2 renal tubular cells (endogenous and exogenous levels), and co-expression of Erbin blocks Sema4C-induced EMT; Erbin siRNA potentiates Sema4C-driven EMT, indicating that Erbin is a negative regulator of Sema4C signaling.","method":"Co-immunoprecipitation (endogenous and exogenous), siRNA knockdown, plasmid overexpression, Western blotting, ELISA","journal":"Journal of Huazhong University of Science and Technology. Medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue/KD, single lab","pmids":["24142719"],"is_preprint":false},{"year":2018,"finding":"Sema4C signals through PlexinB2 to maintain RhoA-GTP levels required for G2/M phase transition and cytokinesis in breast carcinoma cells; knockdown of Sema4C or PlexinB2 causes growth inhibition, cytokinesis defects, and cell senescence via a Sema4C/PlexinB2/LARG-dependent cascade. Sema4C overexpression in luminal breast cancer cells drives disassembly of polarity complexes, mitotic spindle misorientation, cell–cell dissociation, and increased invasiveness dependent on PlexinB2 effectors ErbB2 and RhoA-dependent kinases.","method":"shRNA/siRNA knockdown, Sema4C overexpression, RhoA-GTP pull-down assay, cell cycle analysis, pharmacological inhibitors, xenograft mouse model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, OE, biochemical RhoA-GTP assay, in vivo xenograft) identifying a defined signaling cascade","pmids":["29555978"],"is_preprint":false},{"year":2016,"finding":"Tumor-associated lymphatic endothelial cells secrete soluble SEMA4C (sSEMA4C) that promotes lymphangiogenesis by activating PlexinB2-ERBB2 signaling and promotes tumor cell proliferation/migration by activating PlexinB2-MET signaling; RhoA activation is required for SEMA4C effects in both cell types.","method":"cDNA microarray of laser-capture-microdissected LECs, ELISA, migration assay, tube-formation assay, immunoblotting, fluorescence imaging of lymph node metastasis","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro assays plus identified downstream signaling effectors, single lab","pmids":["27401250"],"is_preprint":false},{"year":2019,"finding":"SEMA4C knockdown in osteosarcoma cells reduces AKT signaling, causes G1 cell cycle arrest, and decreases expression of mesenchymal markers SNAI1, SNAI2, and TWIST1; monoclonal antibody blockade of SEMA4C mirrors these genetic effects; SEMA4C overexpression promotes cellular transformation properties.","method":"RNAi knockdown, overexpression, monoclonal antibody blockade, Western blotting for pAKT, cell cycle analysis, colony formation, wound healing, Transwell migration, xenograft tumor growth and lung metastasis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KD and OE plus antibody blockade and in vivo xenograft/metastasis, multiple orthogonal methods converging on AKT pathway","pmids":["31582836"],"is_preprint":false},{"year":2020,"finding":"Downregulation of SEMA4C in HeLa cervical cancer cells inhibits TGF-β1-induced p38 MAPK activation, reverses EMT (restores E-cadherin, reduces fibronectin), and reduces migration and invasion.","method":"Stable shRNA knockdown (Hela-shSEMA4C), TGF-β1 stimulation, Western blotting for p-p38, immunofluorescence, ELISA, scratch/invasion assays","journal":"Medical science monitor","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular readout (p38 phosphorylation) and multiple functional assays, single lab","pmids":["31951596"],"is_preprint":false},{"year":2021,"finding":"Sema4C promotes migration of tumor-associated lymphatic endothelial cells (TLECs) via an ERK/E-cadherin pathway: overexpression of Sema4C stimulates TLEC migration, downregulates E-cadherin, and stimulates ERK phosphorylation; knockdown has opposite effects; ERK inhibitor PD98059 blocks the pro-migratory effect.","method":"Lentiviral Sema4C overexpression/knockdown in primary TLECs, Transwell migration assay, Western blotting, pharmacological ERK inhibition (PD98059), confocal imaging","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — OE, KD, and pharmacological inhibition converging on ERK pathway, single lab","pmids":["34504556"],"is_preprint":false},{"year":2022,"finding":"Sema4C is required for normal vascular patterning and primary motor neuron axon guidance in zebrafish: morpholino knockdown of sema4C causes pathfinding defects in intersegmental vessels and primary motor neurons, and these are rescued by exogenous sema4C mRNA.","method":"Morpholino knockdown, mRNA rescue, in situ hybridization, fluorescence imaging in zebrafish embryos","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD plus mRNA rescue with defined vascular and neural phenotypes in zebrafish, single lab","pmids":["36010604"],"is_preprint":false},{"year":2025,"finding":"USP32 directly interacts with SEMA4C in colorectal cancer cells and stabilizes it by removing K48-linked polyubiquitin chains, thereby preventing proteasomal degradation; USP32 knockdown increases SEMA4C ubiquitination and accelerates its degradation, reducing malignant behaviors that can be restored by SEMA4C overexpression.","method":"Co-immunoprecipitation (USP32–SEMA4C interaction), ubiquitination assay (K48-specific), USP32 knockdown, SEMA4C overexpression rescue, cell viability/cell cycle/migration/invasion assays, Western blotting","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction plus ubiquitination mechanistic assay and rescue experiment, single lab","pmids":["40819507"],"is_preprint":false}],"current_model":"SEMA4C is a transmembrane semaphorin that signals primarily through its receptor PlexinB2, activating downstream effectors including RhoA (via LARG), p38 MAPK, ERK, AKT, ErbB2, and MET to regulate diverse processes—myogenic differentiation, epithelial-mesenchymal transition, ureteric branching, lymphatic endothelial cell migration, vascular and neuronal patterning, and cancer cell growth and metastasis—while its intracellular domain interacts with PDZ-domain proteins (PSD-95 family, Erbin) and its protein stability is controlled by USP32-mediated deubiquitination of K48-linked polyubiquitin chains."},"narrative":{"mechanistic_narrative":"SEMA4C is a transmembrane semaphorin that functions as a cell-surface and soluble signaling ligand controlling cell differentiation, migration, and tissue patterning across developmental and oncogenic contexts [PMID:17498836, PMID:27401250]. Its principal receptor is PlexinB2, through which SEMA4C maintains RhoA-GTP levels and engages the receptor tyrosine kinases ErbB2 and MET to drive cytokinesis, polarity-complex disassembly, lymphangiogenesis, and tumor cell proliferation and invasion [PMID:29555978, PMID:27401250]. A recurrent output of SEMA4C signaling is activation of the p38 MAPK cascade, which it uses both to promote terminal myogenic differentiation via the myogenin promoter [PMID:17498836] and to drive TGF-β1-induced epithelial-mesenchymal transition in renal tubular and cervical cancer cells [PMID:20959347, PMID:31951596]; in parallel it signals through ERK to downregulate E-cadherin and promote lymphatic endothelial migration [PMID:34504556] and through AKT to sustain mesenchymal marker expression and cell-cycle progression in osteosarcoma [PMID:31582836]. During organogenesis SEMA4C-PlexinB2 signaling stimulates ureteric epithelial branching in concert with Ret receptor tyrosine kinase [PMID:21035938] and is required for intersegmental vessel and motor-axon pathfinding [PMID:36010604]. The intracellular C-terminal region binds PDZ-domain scaffolds of the PSD-95 family and localizes SEMA4C to synaptic compartments [PMID:11134026], while the PDZ protein Erbin binds SEMA4C and acts as a negative regulator of its EMT-promoting signaling [PMID:24142719]. SEMA4C protein abundance is controlled post-translationally by USP32, which removes K48-linked polyubiquitin chains to prevent proteasomal degradation [PMID:40819507].","teleology":[{"year":2000,"claim":"Established the first molecular partners of SEMA4C, showing its cytoplasmic tail engages PDZ-domain scaffolds and that the protein localizes to synaptic structures, implicating it in neuronal organization.","evidence":"Co-IP, subcellular fractionation, and colocalization with PSD-95 in mouse neocortical neurons","pmids":["11134026"],"confidence":"Medium","gaps":["Functional consequence of PDZ binding at synapses not tested","No downstream signaling defined","Receptor not identified in this study"]},{"year":2005,"claim":"Demonstrated SEMA4C is functionally required for terminal myogenic differentiation, and that both its extracellular Sema domain and intracellular C-terminus contribute, framing it as a cell-cell interaction signal.","evidence":"siRNA knockdown and dominant-negative peptide/fusion inhibition in C2C12 myoblasts plus in vivo regeneration","pmids":["15811348"],"confidence":"Medium","gaps":["Downstream signaling pathway not yet defined","Receptor mediating the effect not identified"]},{"year":2007,"claim":"Resolved the differentiation mechanism by placing p38 MAPK and the myogenin promoter downstream of SEMA4C, the first defined SEMA4C effector pathway.","evidence":"Overexpression, knockdown, SB203580 inhibition, and myogenin reporter assays in C2C12 cells with in vivo regeneration","pmids":["17498836"],"confidence":"High","gaps":["Receptor coupling SEMA4C to p38 not identified","Mechanism of p38 activation unresolved"]},{"year":2010,"claim":"Extended the p38 axis to pathology, showing SEMA4C is a TGF-β1-induced driver of EMT in renal tubular epithelium, and independently identified PlexinB2 as a SEMA4C receptor governing ureteric branching in kidney development.","evidence":"Knockdown/overexpression with SB203580 and nephrectomy model (EMT); Plxnb2 knockout explants and PlexinB2-Ret Co-IP (branching)","pmids":["20959347","21035938"],"confidence":"High","gaps":["Whether the EMT and branching arms share PlexinB2 not directly tested","Mechanism linking PlexinB2 to Ret modulation unresolved"]},{"year":2013,"claim":"Identified Erbin as a direct binding partner that negatively regulates SEMA4C-driven EMT, adding a brake to the pathway.","evidence":"Endogenous and exogenous Co-IP with siRNA and overexpression rescue in HK2 cells","pmids":["24142719"],"confidence":"Medium","gaps":["Molecular mechanism of inhibition not defined","Single lab, single cell type"]},{"year":2016,"claim":"Showed SEMA4C acts as a secreted soluble ligand in the tumor microenvironment, bifurcating PlexinB2 signaling into ERBB2-driven lymphangiogenesis and MET-driven tumor cell proliferation/migration, both RhoA-dependent.","evidence":"LEC microarray, ELISA, migration and tube-formation assays, and metastasis imaging","pmids":["27401250"],"confidence":"Medium","gaps":["Mechanism of soluble SEMA4C generation not defined","Receptor-effector coupling not structurally resolved"]},{"year":2018,"claim":"Defined a SEMA4C/PlexinB2/LARG/RhoA cascade required for G2/M transition and cytokinesis in breast carcinoma, linking SEMA4C to mitotic fidelity and invasiveness through ErbB2 and RhoA-dependent kinases.","evidence":"Knockdown, overexpression, RhoA-GTP pull-down, cell cycle analysis, inhibitors, and xenograft","pmids":["29555978"],"confidence":"High","gaps":["How RhoA-GTP is spatially controlled during cytokinesis not resolved","Relationship to p38/ERK arms not integrated"]},{"year":2019,"claim":"Added AKT as a SEMA4C effector controlling cell-cycle progression and mesenchymal marker expression in osteosarcoma, and validated antibody blockade as phenocopying genetic loss, nominating SEMA4C as a therapeutic target.","evidence":"RNAi, overexpression, monoclonal antibody blockade, pAKT immunoblot, and xenograft/metastasis assays","pmids":["31582836"],"confidence":"High","gaps":["Receptor coupling SEMA4C to AKT not identified","Relationship of AKT arm to RhoA and p38 arms unresolved"]},{"year":2020,"claim":"Confirmed the TGF-β1/SEMA4C/p38 EMT axis operates in cervical cancer, generalizing the renal-tubule mechanism to a second epithelial cancer context.","evidence":"Stable shRNA knockdown with TGF-β1 stimulation, p-p38 immunoblot, and migration/invasion assays in HeLa","pmids":["31951596"],"confidence":"Medium","gaps":["Receptor mediating p38 activation not identified","Single cell line"]},{"year":2021,"claim":"Distinguished an ERK/E-cadherin migratory arm in tumor-associated lymphatic endothelial cells, complementing the earlier soluble SEMA4C lymphangiogenesis findings.","evidence":"Lentiviral overexpression/knockdown, Transwell migration, immunoblot, and PD98059 ERK inhibition in primary TLECs","pmids":["34504556"],"confidence":"Medium","gaps":["Receptor upstream of ERK not defined","Integration with PlexinB2-ERBB2 lymphangiogenic signaling unresolved"]},{"year":2022,"claim":"Established an in vivo developmental requirement for SEMA4C in coordinated vascular and neuronal axon guidance, consistent with its canonical semaphorin guidance role.","evidence":"Morpholino knockdown with mRNA rescue and in situ hybridization in zebrafish embryos","pmids":["36010604"],"confidence":"Medium","gaps":["Receptor and downstream effector in guidance not identified","Cell-autonomy of the phenotype not resolved"]},{"year":2025,"claim":"Identified the first post-translational regulator of SEMA4C abundance, showing USP32 deubiquitinates K48-linked chains to stabilize SEMA4C and sustain malignancy in colorectal cancer.","evidence":"Co-IP, K48-specific ubiquitination assay, USP32 knockdown, and SEMA4C overexpression rescue with functional assays","pmids":["40819507"],"confidence":"Medium","gaps":["E3 ligase opposing USP32 not identified","Whether stabilization alters specific downstream arms not tested"]},{"year":null,"claim":"It remains unresolved how SEMA4C selects between its multiple downstream arms (p38, ERK, AKT, RhoA via ErbB2/MET) in a given cell type, and what determines membrane-bound versus soluble signaling modes.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model integrating the distinct effector pathways","Mechanism generating soluble SEMA4C undefined","Structural basis of PlexinB2 versus PDZ-scaffold engagement unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8]}],"complexes":[],"partners":["PLXNB2","ERBB2","MET","RET","ERBIN","DLG4","USP32"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C0C4","full_name":"Semaphorin-4C","aliases":[],"length_aa":833,"mass_kda":92.6,"function":"Cell surface receptor for PLXNB2 that plays an important role in cell-cell signaling. PLXNB2 binding promotes downstream activation of RHOA and phosphorylation of ERBB2 at 'Tyr-1248'. Required for normal brain development, axon guidance and cell migration (By similarity). Probable signaling receptor which may play a role in myogenic differentiation through activation of the stress-activated MAPK cascade","subcellular_location":"Postsynaptic density membrane; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q9C0C4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMA4C","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEMA4C","total_profiled":1310},"omim":[{"mim_id":"618991","title":"SEMAPHORIN 4G; SEMA4G","url":"https://www.omim.org/entry/618991"},{"mim_id":"610359","title":"RETINITIS PIGMENTOSA 33; RP33","url":"https://www.omim.org/entry/610359"},{"mim_id":"604462","title":"SEMAPHORIN 4C; SEMA4C","url":"https://www.omim.org/entry/604462"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEMA4C"},"hgnc":{"alias_symbol":["Semacl1","Semaf"],"prev_symbol":["SEMAI"]},"alphafold":{"accession":"Q9C0C4","domains":[{"cath_id":"3.30.1680.10","chopping":"500-553","consensus_level":"high","plddt":85.3269,"start":500,"end":553},{"cath_id":"2.60.40.10","chopping":"564-647","consensus_level":"high","plddt":87.8782,"start":564,"end":647}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0C4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0C4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0C4-F1-predicted_aligned_error_v6.png","plddt_mean":81.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMA4C","jax_strain_url":"https://www.jax.org/strain/search?query=SEMA4C"},"sequence":{"accession":"Q9C0C4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C0C4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C0C4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0C4"}},"corpus_meta":[{"pmid":"25605244","id":"PMC_25605244","title":"MiR-125b regulates epithelial-mesenchymal transition via targeting Sema4C in paclitaxel-resistant breast cancer cells.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25605244","citation_count":86,"is_preprint":false},{"pmid":"26283050","id":"PMC_26283050","title":"MiR-138 inhibits cell proliferation and reverses epithelial-mesenchymal transition in non-small cell lung cancer cells by targeting GIT1 and SEMA4C.","date":"2015","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26283050","citation_count":72,"is_preprint":false},{"pmid":"27743413","id":"PMC_27743413","title":"miR-25-3p reverses epithelial-mesenchymal transition via targeting Sema4C in cisplatin-resistance cervical cancer cells.","date":"2016","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/27743413","citation_count":72,"is_preprint":false},{"pmid":"29555978","id":"PMC_29555978","title":"Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29555978","citation_count":66,"is_preprint":false},{"pmid":"11134026","id":"PMC_11134026","title":"Sema4c, a transmembrane semaphorin, interacts with a post-synaptic density protein, PSD-95.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11134026","citation_count":54,"is_preprint":false},{"pmid":"27401250","id":"PMC_27401250","title":"Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27401250","citation_count":48,"is_preprint":false},{"pmid":"20478304","id":"PMC_20478304","title":"A systematic expression analysis implicates Plexin-B2 and its ligand Sema4C in the regulation of the vascular and endocrine system.","date":"2010","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/20478304","citation_count":40,"is_preprint":false},{"pmid":"17498836","id":"PMC_17498836","title":"Sema4C participates in myogenic differentiation in vivo and in vitro through the p38 MAPK pathway.","date":"2007","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17498836","citation_count":35,"is_preprint":false},{"pmid":"20959347","id":"PMC_20959347","title":"Role of Sema4C in TGF-β1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells.","date":"2010","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/20959347","citation_count":35,"is_preprint":false},{"pmid":"21035938","id":"PMC_21035938","title":"Sema4C-Plexin B2 signalling modulates ureteric branching in developing kidney.","date":"2010","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/21035938","citation_count":30,"is_preprint":false},{"pmid":"29799789","id":"PMC_29799789","title":"MiR-205 suppresses tumor growth, invasion, and epithelial-mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29799789","citation_count":30,"is_preprint":false},{"pmid":"31776419","id":"PMC_31776419","title":"Sema4C mediates EMT inducing chemotherapeutic resistance of miR-31-3p in cervical cancer cells.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31776419","citation_count":29,"is_preprint":false},{"pmid":"31908535","id":"PMC_31908535","title":"LncRNA FOXD2-AS1 Regulates miR-25-3p/Sema4c Axis To Promote The Invasion And Migration Of Colorectal Cancer Cells.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31908535","citation_count":24,"is_preprint":false},{"pmid":"15811348","id":"PMC_15811348","title":"Requirement of the transmembrane semaphorin Sema4C for myogenic differentiation.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15811348","citation_count":24,"is_preprint":false},{"pmid":"19660153","id":"PMC_19660153","title":"Molecular characterization of Giardia duodenalis isolated from Semai Pahang Orang Asli (Peninsular Malaysia aborigines).","date":"2009","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/19660153","citation_count":23,"is_preprint":false},{"pmid":"19189244","id":"PMC_19189244","title":"Sema4C expression in neural stem/progenitor cells and in adult neurogenesis induced by cerebral ischemia.","date":"2009","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/19189244","citation_count":18,"is_preprint":false},{"pmid":"34584571","id":"PMC_34584571","title":"lncRNA CYTOR promotes cell proliferation and tumor growth via miR-125b/SEMA4C axis in hepatocellular carcinoma.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34584571","citation_count":18,"is_preprint":false},{"pmid":"22944267","id":"PMC_22944267","title":"[Expression and clinical significance of Sema4C in esophageal cancer, gastric cancer and rectal cancer].","date":"2012","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/22944267","citation_count":16,"is_preprint":false},{"pmid":"32683841","id":"PMC_32683841","title":"Hsa-miR-10a-5p promotes pancreatic cancer growth by BDNF/SEMA4C pathway.","date":"2020","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/32683841","citation_count":16,"is_preprint":false},{"pmid":"31582836","id":"PMC_31582836","title":"SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31582836","citation_count":13,"is_preprint":false},{"pmid":"31951596","id":"PMC_31951596","title":"Downregulation of SEMA4C Inhibit Epithelial-Mesenchymal Transition (EMT) and the Invasion and Metastasis of Cervical Cancer Cells via Inhibiting Transforming Growth Factor-beta 1 (TGF-β1)-Induced Hela cells p38 Mitogen-Activated Protein Kinase (MAPK) Activation.","date":"2020","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/31951596","citation_count":12,"is_preprint":false},{"pmid":"32863907","id":"PMC_32863907","title":"miR-642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38 MAPK signaling pathway.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32863907","citation_count":12,"is_preprint":false},{"pmid":"33394293","id":"PMC_33394293","title":"Long non-coding RNA TDRG1 promotes hypoxia-induced glycolysis by targeting the miR-214-5p/SEMA4C axis in cervical cancer cells.","date":"2021","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/33394293","citation_count":10,"is_preprint":false},{"pmid":"24142719","id":"PMC_24142719","title":"Erbin interacts with Sema4C and inhibits Sema4C-induced epithelial-mesenchymal transition in HK2 cells.","date":"2013","source":"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","url":"https://pubmed.ncbi.nlm.nih.gov/24142719","citation_count":9,"is_preprint":false},{"pmid":"7721278","id":"PMC_7721278","title":"Population genetic study among the Orange Asli (Semai Senoi) of Malaysia: Malayan aborigines.","date":"1995","source":"Human biology","url":"https://pubmed.ncbi.nlm.nih.gov/7721278","citation_count":7,"is_preprint":false},{"pmid":"37304850","id":"PMC_37304850","title":"Nutritional Profiles of Four Promising Wild Edible Plants Commonly Consumed by the Semai in Malaysia.","date":"2023","source":"Current developments in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/37304850","citation_count":5,"is_preprint":false},{"pmid":"37595073","id":"PMC_37595073","title":"Circ-POLA2-mediated miR-138-5p/SEMA4C axis affects colon cancer cell activities.","date":"2023","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/37595073","citation_count":4,"is_preprint":false},{"pmid":"34504556","id":"PMC_34504556","title":"Sema4C modulates the migration of primary tumor-associated lymphatic endothelial cells via an ERK-mediated pathway.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34504556","citation_count":4,"is_preprint":false},{"pmid":"36010604","id":"PMC_36010604","title":"Sema4C Is Required for Vascular and Primary Motor Neuronal Patterning in Zebrafish.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36010604","citation_count":1,"is_preprint":false},{"pmid":"40819507","id":"PMC_40819507","title":"USP32 stabilizes SEMA4C to promote malignant behavior of colon cancer cells.","date":"2025","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/40819507","citation_count":1,"is_preprint":false},{"pmid":"618819","id":"PMC_618819","title":"Adenosine deaminase polymorphism among the Semai, Temuan, Semelai, and Jakun groups of West Malaysian Orang Asli.","date":"1978","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/618819","citation_count":1,"is_preprint":false},{"pmid":"39018715","id":"PMC_39018715","title":"miR-129-2-3p binds SEMA4C to regulate HCC development and inhibit the EMT.","date":"2024","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/39018715","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18380,"output_tokens":3589,"usd":0.054488,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11169,"output_tokens":4143,"usd":0.07971,"stage2_stop_reason":"end_turn"},"total_usd":0.134198,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Sema4C interacts with PSD-95 family members (PSD-95/SAP90, PSD-93/chapsin110, SAP97/DLG-1) via their PDZ domains; Sema4C is enriched in the synaptic vesicle fraction and Triton X-100-insoluble post-synaptic density fraction of mouse neocortex, and colocalizes with PSD-95 in cortical neurons with a dot-like pattern along neurites.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, immunostaining, colocalization in neocortical culture\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and fractionation in a single lab, two orthogonal methods (biochemical fractionation + immunostaining)\",\n      \"pmids\": [\"11134026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Sema4C is required for myogenic differentiation: depletion of Sema4C in C2C12 myoblasts markedly attenuated myotube formation, and both the extracellular Sema domain fusion protein and a peptide corresponding to the intracellular C-terminal region each inhibited C2C12 differentiation, indicating that Sema4C-mediated cell–cell interaction is necessary for terminal myogenic differentiation.\",\n      \"method\": \"siRNA knockdown of Sema4C in C2C12 cells, dominant-negative peptide/fusion protein inhibition, in vivo muscle regeneration model\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotypic readout plus domain-based mechanistic dissection, single lab\",\n      \"pmids\": [\"15811348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sema4C promotes terminal myogenic differentiation via the p38 MAPK pathway: overexpression of Sema4C in C2C12 cells directly elicited p38 phosphorylation and accelerated myotube formation; these effects were abolished by the p38α-specific inhibitor SB203580. Knockdown of Sema4C suppressed p38 phosphorylation and dramatically reduced myotube formation. Sema4C activated the myogenin promoter in a p38-dependent manner.\",\n      \"method\": \"Stable and transient Sema4C overexpression, siRNA knockdown, pharmacological p38 inhibition (SB203580), Western blotting, myogenin promoter reporter assay, in vivo muscle regeneration model\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (OE, KD, inhibitor, reporter assay) in a single rigorous study, replicated across in vitro and in vivo contexts\",\n      \"pmids\": [\"17498836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sema4C plays an important role in TGF-β1-induced epithelial-mesenchymal transition (EMT) in renal proximal tubular epithelial cells through activation of p38 MAPK: TGF-β1 upregulates Sema4C, Sema4C knockdown inhibits p38 phosphorylation and reverses EMT, and Sema4C overexpression elicits p38 phosphorylation and promotes EMT; these effects are blocked by the p38 inhibitor SB203580.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, SB203580 p38 inhibitor, Western blotting, immunohistochemistry, ELISA, in vivo 5/6 nephrectomy rat model\",\n      \"journal\": \"Nephrology, dialysis, transplantation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, OE, pharmacological inhibition, in vivo model) in a single study, consistent results across all arms\",\n      \"pmids\": [\"20959347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sema4C-Plexin B2 signaling regulates ureteric branching during kidney development: Sema4C (ligand for Plexin B2) stimulates ureteric epithelial branching in wild-type kidney explants but not in Plxnb2−/− explants; Plexin B2 co-immunoprecipitates with the Ret receptor tyrosine kinase in embryonic kidneys, suggesting modulation of GDNF/Ret signaling.\",\n      \"method\": \"Genetic knockout (Plxnb2−/−), kidney explant branching assay, co-immunoprecipitation (Plexin B2–Ret interaction), histological analysis\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (KO rescue), ex vivo functional assay, and biochemical interaction (Co-IP) in same study\",\n      \"pmids\": [\"21035938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Erbin directly interacts with Sema4C in HK2 renal tubular cells (endogenous and exogenous levels), and co-expression of Erbin blocks Sema4C-induced EMT; Erbin siRNA potentiates Sema4C-driven EMT, indicating that Erbin is a negative regulator of Sema4C signaling.\",\n      \"method\": \"Co-immunoprecipitation (endogenous and exogenous), siRNA knockdown, plasmid overexpression, Western blotting, ELISA\",\n      \"journal\": \"Journal of Huazhong University of Science and Technology. Medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue/KD, single lab\",\n      \"pmids\": [\"24142719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sema4C signals through PlexinB2 to maintain RhoA-GTP levels required for G2/M phase transition and cytokinesis in breast carcinoma cells; knockdown of Sema4C or PlexinB2 causes growth inhibition, cytokinesis defects, and cell senescence via a Sema4C/PlexinB2/LARG-dependent cascade. Sema4C overexpression in luminal breast cancer cells drives disassembly of polarity complexes, mitotic spindle misorientation, cell–cell dissociation, and increased invasiveness dependent on PlexinB2 effectors ErbB2 and RhoA-dependent kinases.\",\n      \"method\": \"shRNA/siRNA knockdown, Sema4C overexpression, RhoA-GTP pull-down assay, cell cycle analysis, pharmacological inhibitors, xenograft mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, OE, biochemical RhoA-GTP assay, in vivo xenograft) identifying a defined signaling cascade\",\n      \"pmids\": [\"29555978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tumor-associated lymphatic endothelial cells secrete soluble SEMA4C (sSEMA4C) that promotes lymphangiogenesis by activating PlexinB2-ERBB2 signaling and promotes tumor cell proliferation/migration by activating PlexinB2-MET signaling; RhoA activation is required for SEMA4C effects in both cell types.\",\n      \"method\": \"cDNA microarray of laser-capture-microdissected LECs, ELISA, migration assay, tube-formation assay, immunoblotting, fluorescence imaging of lymph node metastasis\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro assays plus identified downstream signaling effectors, single lab\",\n      \"pmids\": [\"27401250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SEMA4C knockdown in osteosarcoma cells reduces AKT signaling, causes G1 cell cycle arrest, and decreases expression of mesenchymal markers SNAI1, SNAI2, and TWIST1; monoclonal antibody blockade of SEMA4C mirrors these genetic effects; SEMA4C overexpression promotes cellular transformation properties.\",\n      \"method\": \"RNAi knockdown, overexpression, monoclonal antibody blockade, Western blotting for pAKT, cell cycle analysis, colony formation, wound healing, Transwell migration, xenograft tumor growth and lung metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KD and OE plus antibody blockade and in vivo xenograft/metastasis, multiple orthogonal methods converging on AKT pathway\",\n      \"pmids\": [\"31582836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Downregulation of SEMA4C in HeLa cervical cancer cells inhibits TGF-β1-induced p38 MAPK activation, reverses EMT (restores E-cadherin, reduces fibronectin), and reduces migration and invasion.\",\n      \"method\": \"Stable shRNA knockdown (Hela-shSEMA4C), TGF-β1 stimulation, Western blotting for p-p38, immunofluorescence, ELISA, scratch/invasion assays\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular readout (p38 phosphorylation) and multiple functional assays, single lab\",\n      \"pmids\": [\"31951596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sema4C promotes migration of tumor-associated lymphatic endothelial cells (TLECs) via an ERK/E-cadherin pathway: overexpression of Sema4C stimulates TLEC migration, downregulates E-cadherin, and stimulates ERK phosphorylation; knockdown has opposite effects; ERK inhibitor PD98059 blocks the pro-migratory effect.\",\n      \"method\": \"Lentiviral Sema4C overexpression/knockdown in primary TLECs, Transwell migration assay, Western blotting, pharmacological ERK inhibition (PD98059), confocal imaging\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — OE, KD, and pharmacological inhibition converging on ERK pathway, single lab\",\n      \"pmids\": [\"34504556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sema4C is required for normal vascular patterning and primary motor neuron axon guidance in zebrafish: morpholino knockdown of sema4C causes pathfinding defects in intersegmental vessels and primary motor neurons, and these are rescued by exogenous sema4C mRNA.\",\n      \"method\": \"Morpholino knockdown, mRNA rescue, in situ hybridization, fluorescence imaging in zebrafish embryos\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD plus mRNA rescue with defined vascular and neural phenotypes in zebrafish, single lab\",\n      \"pmids\": [\"36010604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP32 directly interacts with SEMA4C in colorectal cancer cells and stabilizes it by removing K48-linked polyubiquitin chains, thereby preventing proteasomal degradation; USP32 knockdown increases SEMA4C ubiquitination and accelerates its degradation, reducing malignant behaviors that can be restored by SEMA4C overexpression.\",\n      \"method\": \"Co-immunoprecipitation (USP32–SEMA4C interaction), ubiquitination assay (K48-specific), USP32 knockdown, SEMA4C overexpression rescue, cell viability/cell cycle/migration/invasion assays, Western blotting\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction plus ubiquitination mechanistic assay and rescue experiment, single lab\",\n      \"pmids\": [\"40819507\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEMA4C is a transmembrane semaphorin that signals primarily through its receptor PlexinB2, activating downstream effectors including RhoA (via LARG), p38 MAPK, ERK, AKT, ErbB2, and MET to regulate diverse processes—myogenic differentiation, epithelial-mesenchymal transition, ureteric branching, lymphatic endothelial cell migration, vascular and neuronal patterning, and cancer cell growth and metastasis—while its intracellular domain interacts with PDZ-domain proteins (PSD-95 family, Erbin) and its protein stability is controlled by USP32-mediated deubiquitination of K48-linked polyubiquitin chains.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMA4C is a transmembrane semaphorin that functions as a cell-surface and soluble signaling ligand controlling cell differentiation, migration, and tissue patterning across developmental and oncogenic contexts [#2, #7]. Its principal receptor is PlexinB2, through which SEMA4C maintains RhoA-GTP levels and engages the receptor tyrosine kinases ErbB2 and MET to drive cytokinesis, polarity-complex disassembly, lymphangiogenesis, and tumor cell proliferation and invasion [#6, #7]. A recurrent output of SEMA4C signaling is activation of the p38 MAPK cascade, which it uses both to promote terminal myogenic differentiation via the myogenin promoter [#2] and to drive TGF-\\u03b21-induced epithelial-mesenchymal transition in renal tubular and cervical cancer cells [#3, #9]; in parallel it signals through ERK to downregulate E-cadherin and promote lymphatic endothelial migration [#10] and through AKT to sustain mesenchymal marker expression and cell-cycle progression in osteosarcoma [#8]. During organogenesis SEMA4C-PlexinB2 signaling stimulates ureteric epithelial branching in concert with Ret receptor tyrosine kinase [#4] and is required for intersegmental vessel and motor-axon pathfinding [#11]. The intracellular C-terminal region binds PDZ-domain scaffolds of the PSD-95 family and localizes SEMA4C to synaptic compartments [#0], while the PDZ protein Erbin binds SEMA4C and acts as a negative regulator of its EMT-promoting signaling [#5]. SEMA4C protein abundance is controlled post-translationally by USP32, which removes K48-linked polyubiquitin chains to prevent proteasomal degradation [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the first molecular partners of SEMA4C, showing its cytoplasmic tail engages PDZ-domain scaffolds and that the protein localizes to synaptic structures, implicating it in neuronal organization.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, and colocalization with PSD-95 in mouse neocortical neurons\",\n      \"pmids\": [\"11134026\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of PDZ binding at synapses not tested\", \"No downstream signaling defined\", \"Receptor not identified in this study\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated SEMA4C is functionally required for terminal myogenic differentiation, and that both its extracellular Sema domain and intracellular C-terminus contribute, framing it as a cell-cell interaction signal.\",\n      \"evidence\": \"siRNA knockdown and dominant-negative peptide/fusion inhibition in C2C12 myoblasts plus in vivo regeneration\",\n      \"pmids\": [\"15811348\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream signaling pathway not yet defined\", \"Receptor mediating the effect not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the differentiation mechanism by placing p38 MAPK and the myogenin promoter downstream of SEMA4C, the first defined SEMA4C effector pathway.\",\n      \"evidence\": \"Overexpression, knockdown, SB203580 inhibition, and myogenin reporter assays in C2C12 cells with in vivo regeneration\",\n      \"pmids\": [\"17498836\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor coupling SEMA4C to p38 not identified\", \"Mechanism of p38 activation unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the p38 axis to pathology, showing SEMA4C is a TGF-\\u03b21-induced driver of EMT in renal tubular epithelium, and independently identified PlexinB2 as a SEMA4C receptor governing ureteric branching in kidney development.\",\n      \"evidence\": \"Knockdown/overexpression with SB203580 and nephrectomy model (EMT); Plxnb2 knockout explants and PlexinB2-Ret Co-IP (branching)\",\n      \"pmids\": [\"20959347\", \"21035938\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether the EMT and branching arms share PlexinB2 not directly tested\", \"Mechanism linking PlexinB2 to Ret modulation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified Erbin as a direct binding partner that negatively regulates SEMA4C-driven EMT, adding a brake to the pathway.\",\n      \"evidence\": \"Endogenous and exogenous Co-IP with siRNA and overexpression rescue in HK2 cells\",\n      \"pmids\": [\"24142719\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism of inhibition not defined\", \"Single lab, single cell type\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed SEMA4C acts as a secreted soluble ligand in the tumor microenvironment, bifurcating PlexinB2 signaling into ERBB2-driven lymphangiogenesis and MET-driven tumor cell proliferation/migration, both RhoA-dependent.\",\n      \"evidence\": \"LEC microarray, ELISA, migration and tube-formation assays, and metastasis imaging\",\n      \"pmids\": [\"27401250\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of soluble SEMA4C generation not defined\", \"Receptor-effector coupling not structurally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a SEMA4C/PlexinB2/LARG/RhoA cascade required for G2/M transition and cytokinesis in breast carcinoma, linking SEMA4C to mitotic fidelity and invasiveness through ErbB2 and RhoA-dependent kinases.\",\n      \"evidence\": \"Knockdown, overexpression, RhoA-GTP pull-down, cell cycle analysis, inhibitors, and xenograft\",\n      \"pmids\": [\"29555978\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How RhoA-GTP is spatially controlled during cytokinesis not resolved\", \"Relationship to p38/ERK arms not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added AKT as a SEMA4C effector controlling cell-cycle progression and mesenchymal marker expression in osteosarcoma, and validated antibody blockade as phenocopying genetic loss, nominating SEMA4C as a therapeutic target.\",\n      \"evidence\": \"RNAi, overexpression, monoclonal antibody blockade, pAKT immunoblot, and xenograft/metastasis assays\",\n      \"pmids\": [\"31582836\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor coupling SEMA4C to AKT not identified\", \"Relationship of AKT arm to RhoA and p38 arms unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed the TGF-\\u03b21/SEMA4C/p38 EMT axis operates in cervical cancer, generalizing the renal-tubule mechanism to a second epithelial cancer context.\",\n      \"evidence\": \"Stable shRNA knockdown with TGF-\\u03b21 stimulation, p-p38 immunoblot, and migration/invasion assays in HeLa\",\n      \"pmids\": [\"31951596\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor mediating p38 activation not identified\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinguished an ERK/E-cadherin migratory arm in tumor-associated lymphatic endothelial cells, complementing the earlier soluble SEMA4C lymphangiogenesis findings.\",\n      \"evidence\": \"Lentiviral overexpression/knockdown, Transwell migration, immunoblot, and PD98059 ERK inhibition in primary TLECs\",\n      \"pmids\": [\"34504556\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor upstream of ERK not defined\", \"Integration with PlexinB2-ERBB2 lymphangiogenic signaling unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established an in vivo developmental requirement for SEMA4C in coordinated vascular and neuronal axon guidance, consistent with its canonical semaphorin guidance role.\",\n      \"evidence\": \"Morpholino knockdown with mRNA rescue and in situ hybridization in zebrafish embryos\",\n      \"pmids\": [\"36010604\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor and downstream effector in guidance not identified\", \"Cell-autonomy of the phenotype not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the first post-translational regulator of SEMA4C abundance, showing USP32 deubiquitinates K48-linked chains to stabilize SEMA4C and sustain malignancy in colorectal cancer.\",\n      \"evidence\": \"Co-IP, K48-specific ubiquitination assay, USP32 knockdown, and SEMA4C overexpression rescue with functional assays\",\n      \"pmids\": [\"40819507\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"E3 ligase opposing USP32 not identified\", \"Whether stabilization alters specific downstream arms not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SEMA4C selects between its multiple downstream arms (p38, ERK, AKT, RhoA via ErbB2/MET) in a given cell type, and what determines membrane-bound versus soluble signaling modes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model integrating the distinct effector pathways\", \"Mechanism generating soluble SEMA4C undefined\", \"Structural basis of PlexinB2 versus PDZ-scaffold engagement unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLXNB2\", \"ERBB2\", \"MET\", \"RET\", \"ERBIN\", \"DLG4\", \"USP32\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}