Affinage

SEMA4C

Semaphorin-4C · UniProt Q9C0C4

Length
833 aa
Mass
92.6 kDa
Annotated
2026-06-10
32 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 Medium

    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

    PMID:11134026

    Open questions at the time
    • Functional consequence of PDZ binding at synapses not tested
    • No downstream signaling defined
    • Receptor not identified in this study
  2. 2005 Medium

    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

    PMID:15811348

    Open questions at the time
    • Downstream signaling pathway not yet defined
    • Receptor mediating the effect not identified
  3. 2007 High

    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

    PMID:17498836

    Open questions at the time
    • Receptor coupling SEMA4C to p38 not identified
    • Mechanism of p38 activation unresolved
  4. 2010 High

    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)

    PMID:20959347 PMID:21035938

    Open questions at the time
    • Whether the EMT and branching arms share PlexinB2 not directly tested
    • Mechanism linking PlexinB2 to Ret modulation unresolved
  5. 2013 Medium

    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

    PMID:24142719

    Open questions at the time
    • Molecular mechanism of inhibition not defined
    • Single lab, single cell type
  6. 2016 Medium

    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

    PMID:27401250

    Open questions at the time
    • Mechanism of soluble SEMA4C generation not defined
    • Receptor-effector coupling not structurally resolved
  7. 2018 High

    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

    PMID:29555978

    Open questions at the time
    • How RhoA-GTP is spatially controlled during cytokinesis not resolved
    • Relationship to p38/ERK arms not integrated
  8. 2019 High

    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

    PMID:31582836

    Open questions at the time
    • Receptor coupling SEMA4C to AKT not identified
    • Relationship of AKT arm to RhoA and p38 arms unresolved
  9. 2020 Medium

    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

    PMID:31951596

    Open questions at the time
    • Receptor mediating p38 activation not identified
    • Single cell line
  10. 2021 Medium

    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

    PMID:34504556

    Open questions at the time
    • Receptor upstream of ERK not defined
    • Integration with PlexinB2-ERBB2 lymphangiogenic signaling unresolved
  11. 2022 Medium

    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

    PMID:36010604

    Open questions at the time
    • Receptor and downstream effector in guidance not identified
    • Cell-autonomy of the phenotype not resolved
  12. 2025 Medium

    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

    PMID:40819507

    Open questions at the time
    • E3 ligase opposing USP32 not identified
    • Whether stabilization alters specific downstream arms not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unifying model integrating the distinct effector pathways
  • Mechanism generating soluble SEMA4C undefined
  • Structural basis of PlexinB2 versus PDZ-scaffold engagement unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 2 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005576 extracellular region 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2
Partners
DLG4ERBB2ERBINMETPLXNB2RETUSP32

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Co-immunoprecipitation, subcellular fractionation, immunostaining, colocalization in neocortical culture The Journal of biological chemistry Medium 11134026
2005 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. siRNA knockdown of Sema4C in C2C12 cells, dominant-negative peptide/fusion protein inhibition, in vivo muscle regeneration model FEBS letters Medium 15811348
2007 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. Stable and transient Sema4C overexpression, siRNA knockdown, pharmacological p38 inhibition (SB203580), Western blotting, myogenin promoter reporter assay, in vivo muscle regeneration model European journal of cell biology High 17498836
2010 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. siRNA knockdown, plasmid overexpression, SB203580 p38 inhibitor, Western blotting, immunohistochemistry, ELISA, in vivo 5/6 nephrectomy rat model Nephrology, dialysis, transplantation High 20959347
2010 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. Genetic knockout (Plxnb2−/−), kidney explant branching assay, co-immunoprecipitation (Plexin B2–Ret interaction), histological analysis Differentiation; research in biological diversity High 21035938
2013 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. Co-immunoprecipitation (endogenous and exogenous), siRNA knockdown, plasmid overexpression, Western blotting, ELISA Journal of Huazhong University of Science and Technology. Medical sciences Medium 24142719
2018 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. shRNA/siRNA knockdown, Sema4C overexpression, RhoA-GTP pull-down assay, cell cycle analysis, pharmacological inhibitors, xenograft mouse model Cell death and differentiation High 29555978
2016 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. cDNA microarray of laser-capture-microdissected LECs, ELISA, migration assay, tube-formation assay, immunoblotting, fluorescence imaging of lymph node metastasis Clinical cancer research Medium 27401250
2019 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. 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 Oncogene High 31582836
2020 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. Stable shRNA knockdown (Hela-shSEMA4C), TGF-β1 stimulation, Western blotting for p-p38, immunofluorescence, ELISA, scratch/invasion assays Medical science monitor Medium 31951596
2021 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. Lentiviral Sema4C overexpression/knockdown in primary TLECs, Transwell migration assay, Western blotting, pharmacological ERK inhibition (PD98059), confocal imaging Experimental and therapeutic medicine Medium 34504556
2022 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. Morpholino knockdown, mRNA rescue, in situ hybridization, fluorescence imaging in zebrafish embryos Cells Medium 36010604
2025 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. Co-immunoprecipitation (USP32–SEMA4C interaction), ubiquitination assay (K48-specific), USP32 knockdown, SEMA4C overexpression rescue, cell viability/cell cycle/migration/invasion assays, Western blotting Pathology, research and practice Medium 40819507

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 MiR-125b regulates epithelial-mesenchymal transition via targeting Sema4C in paclitaxel-resistant breast cancer cells. Oncotarget 86 25605244
2016 miR-25-3p reverses epithelial-mesenchymal transition via targeting Sema4C in cisplatin-resistance cervical cancer cells. Cancer science 72 27743413
2015 MiR-138 inhibits cell proliferation and reverses epithelial-mesenchymal transition in non-small cell lung cancer cells by targeting GIT1 and SEMA4C. Journal of cellular and molecular medicine 72 26283050
2018 Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential. Cell death and differentiation 66 29555978
2000 Sema4c, a transmembrane semaphorin, interacts with a post-synaptic density protein, PSD-95. The Journal of biological chemistry 54 11134026
2016 Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C. Clinical cancer research : an official journal of the American Association for Cancer Research 48 27401250
2010 A systematic expression analysis implicates Plexin-B2 and its ligand Sema4C in the regulation of the vascular and endocrine system. Experimental cell research 40 20478304
2010 Role of Sema4C in TGF-β1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 35 20959347
2007 Sema4C participates in myogenic differentiation in vivo and in vitro through the p38 MAPK pathway. European journal of cell biology 35 17498836
2018 MiR-205 suppresses tumor growth, invasion, and epithelial-mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 29799789
2010 Sema4C-Plexin B2 signalling modulates ureteric branching in developing kidney. Differentiation; research in biological diversity 30 21035938
2019 Sema4C mediates EMT inducing chemotherapeutic resistance of miR-31-3p in cervical cancer cells. Scientific reports 29 31776419
2019 LncRNA FOXD2-AS1 Regulates miR-25-3p/Sema4c Axis To Promote The Invasion And Migration Of Colorectal Cancer Cells. Cancer management and research 24 31908535
2005 Requirement of the transmembrane semaphorin Sema4C for myogenic differentiation. FEBS letters 24 15811348
2009 Molecular characterization of Giardia duodenalis isolated from Semai Pahang Orang Asli (Peninsular Malaysia aborigines). Parasitology 23 19660153
2021 lncRNA CYTOR promotes cell proliferation and tumor growth via miR-125b/SEMA4C axis in hepatocellular carcinoma. Oncology letters 18 34584571
2009 Sema4C expression in neural stem/progenitor cells and in adult neurogenesis induced by cerebral ischemia. Journal of molecular neuroscience : MN 18 19189244
2020 Hsa-miR-10a-5p promotes pancreatic cancer growth by BDNF/SEMA4C pathway. Journal of biological regulators and homeostatic agents 16 32683841
2012 [Expression and clinical significance of Sema4C in esophageal cancer, gastric cancer and rectal cancer]. Zhonghua yi xue za zhi 16 22944267
2019 SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis. Oncogene 13 31582836
2020 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. Medical science monitor : international medical journal of experimental and clinical research 12 31951596
2020 miR-642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38 MAPK signaling pathway. Oncology letters 12 32863907
2021 Long non-coding RNA TDRG1 promotes hypoxia-induced glycolysis by targeting the miR-214-5p/SEMA4C axis in cervical cancer cells. Journal of molecular histology 10 33394293
2013 Erbin interacts with Sema4C and inhibits Sema4C-induced epithelial-mesenchymal transition in HK2 cells. 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 9 24142719
1995 Population genetic study among the Orange Asli (Semai Senoi) of Malaysia: Malayan aborigines. Human biology 7 7721278
2023 Nutritional Profiles of Four Promising Wild Edible Plants Commonly Consumed by the Semai in Malaysia. Current developments in nutrition 5 37304850
2023 Circ-POLA2-mediated miR-138-5p/SEMA4C axis affects colon cancer cell activities. Acta biochimica Polonica 4 37595073
2021 Sema4C modulates the migration of primary tumor-associated lymphatic endothelial cells via an ERK-mediated pathway. Experimental and therapeutic medicine 4 34504556
2025 USP32 stabilizes SEMA4C to promote malignant behavior of colon cancer cells. Pathology, research and practice 1 40819507
2022 Sema4C Is Required for Vascular and Primary Motor Neuronal Patterning in Zebrafish. Cells 1 36010604
1978 Adenosine deaminase polymorphism among the Semai, Temuan, Semelai, and Jakun groups of West Malaysian Orang Asli. Human heredity 1 618819
2024 miR-129-2-3p binds SEMA4C to regulate HCC development and inhibit the EMT. Mutation research 0 39018715

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