Affinage

CCN3

CCN family member 3 · UniProt P48745

Length
357 aa
Mass
39.2 kDa
Annotated
2026-06-09
100 papers in source corpus 42 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCN3 (NOV) is a secreted, proteolytically processed matricellular protein that integrates extracellular adhesion cues with intracellular differentiation and proliferation programs in a strongly context-dependent manner (PMID:12695522, PMID:15611078). It functions as a multivalent integrin ligand, binding αvβ3 and α5β1 with nanomolar affinity to support endothelial and fibroblast adhesion, chemotaxis, and in vivo neovascularization, and engaging additional integrins (α6β1, αvβ5, β1, β5) to drive cell-type-specific outputs such as chemokine induction in astrocytes and matrix-modulating enzyme expression in cancer cells (PMID:12695522, PMID:15611078, PMID:20648642). A central mechanism is its action as a non-canonical regulator of Notch: the C-terminal (CT) cysteine-knot module binds the Notch1 extracellular EGF-like repeats to activate HES/Hey transcription, thereby suppressing myogenic and osteogenic differentiation, while in CML cells CCN3 instead reduces NOTCH1-ICD cleavage and downstream c-MYC/HES1 (PMID:12050162, PMID:18275847, PMID:24308033). CCN3 antagonizes pro-fibrotic and pro-osteogenic signaling by directly binding CCN2 (Kd ≈ 2 nM) and BMP-2, down-regulating CCN2 expression, attenuating Smad1/5/8 phosphorylation, and inhibiting collagen and cartilage matrix gene expression downstream of TGF-β; genetic loss in mice accelerates bone regeneration with elevated Smad1/5 phosphorylation (PMID:17250806, PMID:19359517, PMID:20195391, PMID:22812570, PMID:23653360). The protein also acts intracellularly and at the plasma membrane, associating with the Connexin43 C-terminus at gap-junction plaques and activating Rac1 to remodel actin, while amino-truncated CT-bearing variants are targeted to the nucleus where they act as transcriptional repressors (PMID:15213231, PMID:16598765, PMID:19706598). In vascular tissue CCN3 is a protective, shear-stress/KLF2-induced suppressor of NF-κB-driven inflammation and smooth-muscle proliferation, and its loss exacerbates neointima formation, abdominal aortic aneurysm (via ERK1/2), and atherosclerotic foam-cell formation (PMID:21063504, PMID:20139355, PMID:26974158, PMID:28527710). CCN3 is cleaved by MMP14, MMP2 and other MMPs in its variable region, and its expression is controlled transcriptionally by KLF2, FoxO1, and the BCR-ABL/miR-130a/b axis (PMID:21063504, PMID:23705021, PMID:27471094, PMID:21638198).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Establishing that CCN3 physically engages signaling receptors defined its earliest mechanistic identity: it was shown to bind the Notch1 ECD via its CT module and to bind the calcium-binding protein S100A4, linking it to both transcriptional differentiation control and calcium signaling.

    Evidence Co-IP and promoter-reporter assays in myogenic cells; yeast two-hybrid, GST pull-down and calcium imaging in glioblastoma/neuroblastoma cells

    PMID:12050162 PMID:12147716

    Open questions at the time
    • Whether Notch1 binding represents canonical ligand engagement or a distinct mode was unresolved
    • S100A4 interaction not connected to a defined downstream pathway
  2. 2004 High

    Defining CCN3 as a direct integrin ligand and a Connexin43-binding partner established its dual role as an adhesion/migration mediator and a gap-junction-associated protein.

    Evidence Solid-phase integrin binding and blocking assays in endothelial cells and fibroblasts; GST pull-down, Co-IP and domain mapping with Cx43 truncation mutants

    PMID:12695522 PMID:15213231 PMID:15611078

    Open questions at the time
    • Functional consequence of Cx43 binding for channel activity was not resolved here
    • Integrin selectivity differed by cell type without a unifying mechanism
  3. 2006 Medium

    Mapping nuclear targeting to the CT module and showing DDR1-dependent melanocyte positioning revealed that CCN3 acts both as an extracellular adhesion organizer and as a nuclear transcriptional repressor.

    Evidence Truncation constructs with nuclear localization and reporter assays; shRNA knockdown of CCN3 and DDR1 in a 3D skin reconstruct model

    PMID:16598765 PMID:17101694

    Open questions at the time
    • Nuclear target genes of truncated CCN3 not identified
    • How proteolysis generates nuclear variants in vivo unclear
  4. 2006 Medium

    Linking CCN3 to BCR-ABL in CML identified it as a tumor-suppressive node whose loss is driven by oncogenic kinase signaling.

    Evidence Imatinib treatment, BCR-ABL siRNA, CCN3 transfection and colony assays in CML cells

    PMID:16670264

    Open questions at the time
    • Mechanism of CCN3-mediated growth suppression in CML not fully defined at this stage
  5. 2008 High

    Demonstrating a direct, high-affinity CCN2–CCN3 interaction and dissecting parallel BMP- and Notch-dependent routes established CCN3 as a counter-regulator within the CCN family that restrains osteogenic and chondrogenic differentiation.

    Evidence SPR Kd measurement, reciprocal Co-IP, co-localization and chondrocyte gene assays; CT-deletion constructs in mesenchymal stem cells

    PMID:18275847 PMID:22812570

    Open questions at the time
    • Structural basis of CCN2–CCN3 binding unresolved
    • Relative contribution of BMP vs Notch arms varies by context
  6. 2009 High

    Showing that CCN3 down-regulates CCN2 and blocks collagen I downstream of TGF-β, independently of Smad3, positioned CCN3 as an endogenous antifibrotic brake.

    Evidence Exogenous protein and overexpression in mesangial cells with phospho-Smad3 western blot and collagen reporter assays (replicated)

    PMID:19359517 PMID:20195391

    Open questions at the time
    • The Smad3-independent signaling route mediating CCN2 suppression was not identified
  7. 2010 High

    In vitro mechanistic studies and a knockout phenotype converged to define CCN3 as a vascular-protective, Notch- and KLF2-coupled suppressor of inflammation and smooth-muscle proliferation.

    Evidence Recombinant CCN3, γ-secretase inhibition and CCN3-KO neointima model; overexpression/siRNA with NF-κB translocation and KLF2 promoter analysis in endothelial cells

    PMID:20139355 PMID:21063504

    Open questions at the time
    • How CCN3 inhibits NF-κB nuclear translocation mechanistically not resolved
    • Receptor coupling KLF2-induced CCN3 to its anti-inflammatory output unclear
  8. 2011 Medium

    Identifying the BCR-ABL/miR-130a/b axis and integrin αvβ3-dependent HSC maintenance clarified how CCN3 levels are post-transcriptionally controlled and how it sustains stem-cell function.

    Evidence miRNA array and miR-130a/b transfection in leukemia cells; integrin αvβ3 binding and competitive transplantation assays with cytokine regulation

    PMID:21638198 PMID:24563081

    Open questions at the time
    • Whether miR-130 regulation operates in non-leukemic contexts untested
    • Signaling downstream of αvβ3 in HSCs not detailed
  9. 2012 Medium

    Multiple cancer studies established a recurrent integrin→FAK/ILK→Akt→NF-κB module by which CCN3 drives migration, EMT-associated genes, and matrix enzyme/adhesion molecule expression.

    Evidence Integrin-blocking antibodies, kinase inhibitors, NF-κB reporters and ChIP in prostate and chondrosarcoma cells; Rac1/endosome and Cx43 assays in breast cancer cells

    PMID:19706598 PMID:21344378 PMID:22345292

    Open questions at the time
    • Why the same pathway is growth-suppressive in some contexts and pro-metastatic in others unresolved
    • Direct vs indirect integrin engagement not always demonstrated
  10. 2013 Medium

    Transcriptional control by FoxO1 and reduced NOTCH1-ICD cleavage in CML, alongside bone-regeneration phenotypes in KO mice, broadened CCN3's regulatory and tissue roles in metabolism, leukemia and skeletal homeostasis.

    Evidence FoxO1 promoter binding and β-cell functional assays; γ-secretase/BCR-ABL manipulation with NOTCH1-ICD readouts; CCN3 KO and transgenic mice with Smad1/5 analysis

    PMID:23653360 PMID:23705021 PMID:24308033

    Open questions at the time
    • Direct receptor for non-canonical NOTCH1 suppression not fully defined
    • Cause of opposite Notch effects (activation vs ICD reduction) across tissues unexplained
  11. 2016 High

    Structural and degradomic work plus vascular disease models refined the protein's biochemistry and protective vascular function: the VWC domain was crystallized (with no detectable BMP-2 binding), MMP14/MMP2 cleavage sites were mapped, and CCN3 loss was shown to worsen aneurysm and atherosclerosis.

    Evidence X-ray crystallography and direct binding tests; MMP substrate-trapping and in vitro cleavage; Ccn3 KO/transgenic/BM-transplant models with ERK1/2 inhibition and macrophage lipid assays

    PMID:26974158 PMID:27471094 PMID:28527710 PMID:28584056

    Open questions at the time
    • Domain mediating the established BMP-2 association is not the VWC domain
    • Physiological proteases generating active CCN3 fragments in vivo not pinned down
  12. 2023 Medium

    Recent work connected CCN3 to GPNMB/EGFR-MAPK and Wnt/MITF signaling in driving triple-negative breast cancer metastasis, extending its pro-metastatic signaling repertoire.

    Evidence CCN3 knockdown with transcriptome profiling and pathway validation in TNBC cells plus TCGA analysis

    PMID:36737605

    Open questions at the time
    • Receptor mediating CCN3-induced GPNMB/Wnt activation not identified
    • Single-lab finding without orthogonal validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying mechanism reconciling CCN3's opposing context-dependent roles—growth-suppressive vs pro-metastatic, Notch-activating vs Notch-suppressing—remains unresolved.
  • No defined high-affinity signaling receptor accounts for divergent outputs
  • How proteolytic processing and glycosylation switch CCN3 between adhesion, anti-fibrotic, and pro-migratory states is not established
  • Structural basis of integrin/Notch/CCN2 engagement by specific CCN3 modules incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0098631 cell adhesion mediator activity 4 GO:0048018 receptor ligand activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0005768 endosome 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-1474244 Extracellular matrix organization 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4
Partners
BMP2CCN2DDR1GJA1ITGAVNOTCH1POSTNS100A4

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CCN3 directly binds immobilized integrins αvβ3 and α5β1 (half-maximal binding at 10 nM and 50 nM, respectively) and supports endothelial cell adhesion through integrins αvβ3, α5β1, α6β1, and heparan sulfate proteoglycans; CCN3-induced migration is dependent on αvβ3 and α5β1 but not α6β1; CCN3 induces neovascularization in rat cornea in vivo. Solid-phase integrin binding assay, antibody blocking of specific integrins, purified recombinant protein, rat cornea implantation The Journal of biological chemistry High 12695522
2002 CCN3 associates with the EGF-like repeats of Notch1 extracellular domain via its CT (C-terminal cysteine knot) domain; this association activates HES1 and HES5 promoters and suppresses myogenesis by down-regulating MyoD and myogenin. Co-immunoprecipitation, promoter-reporter assays, overexpression in C2/4 myogenic cells The Journal of biological chemistry High 12050162
2004 CCN3 physically interacts with the C-terminal domain of Connexin43 (Cx43); this interaction requires the Cx43 C-terminus (aa 244–382) and causes CCN3 to co-localize with Cx43 in gap junction plaques at the plasma membrane; CCN3 does not associate with Cx40 or Cx32. GST pull-down assay, co-immunoprecipitation, immunocytochemistry with Cx43 truncation mutants, Western blot The Journal of biological chemistry High 15213231
2004 In primary skin fibroblasts, CCN3 supports adhesion through integrins α5β1 and α6β1 and induces chemotaxis through αvβ5; CCN3 is a novel ligand of αvβ5 as shown by solid-phase binding assay; CCN3 up-regulates MMP-1 and PAI-1 and interacts with TGF-β1 in an antagonistic or synergistic manner to regulate specific gene expression. Integrin-blocking antibodies, solid-phase binding assay, chemotaxis assay, gene expression analysis with purified recombinant CCN3 The Journal of biological chemistry High 15611078
2006 CCN3 controls spatial localization of melanocytes to the basement membrane through discoidin domain receptor 1 (DDR1); CCN3 overexpression increases adhesion to collagen IV; DDR1 knockdown decreases melanocyte adhesion to collagen IV and phenocopies CCN3 knockdown. lentiviral shRNA knockdown of CCN3 and DDR1, overexpression, 3D skin reconstruct model, adhesion assays The Journal of cell biology High 17101694
2007 CCN3 associates with BMP-2 (shown by immunoprecipitation-western analysis) and inhibits BMP-2-induced osteoblast differentiation by attenuating Smad1/5/8 phosphorylation and Id1/2/3 expression; CCN3 activates Notch1 cleavage and HES1/Hey1 expression; the inhibitory effect on BMP-2-induced markers is nullified in Hey1-deficient cells. Adenoviral co-transduction, immunoprecipitation-western blot, promoter assays, Hey1-deficient osteoblastic cells Biochemical and biophysical research communications Medium 17250806
2009 In rat mesangial cells, CCN3 (exogenous addition or overexpression) markedly down-regulates CCN2 and blocks collagen type I transcription and accumulation; TGF-β reduces CCN3 while increasing CCN2; this antagonism is not mediated by Smad3 signaling (phospho-Smad3 unaffected). Exogenous recombinant CCN3 treatment, CCN3 overexpression transfection, cell cycle analysis, phospho-Smad3 western blot, collagen type I reporter and protein assays The American journal of pathology High 19359517 20195391
2002 CCN3 interacts with S100A4 (mts1) calcium-binding protein as identified by yeast two-hybrid screening, confirmed by GST pull-down; addition of CCN3 to glioblastoma and neuroblastoma cells causes a transient increase in intracellular calcium from both extracellular entry and intracellular stores. Yeast two-hybrid screen, GST pull-down assay, fluorometric intracellular calcium imaging Molecular pathology Medium 12147716
2006 Amino-truncated variants of CCN3 lacking the N-terminal signal peptide are addressed to the nucleus; the CT (C-terminal) module of CCN3 is responsible for nuclear addressing; nuclear CCN3 variants act as transcriptional regulators with a negative regulatory effect on transcription. Expression of truncated CCN3 constructs with nuclear localization tracking, reporter/transcription assays Journal of cellular biochemistry Medium 16598765
2007 The C-terminal (CT) module of CCN3 is sufficient to induce cell growth inhibition; CCN3 accumulates at the G2/M transition of the cell cycle; CCN3 secretion is regulated by post-translational proteolysis. CCN3 truncation constructs, specific anti-CT antibody reversal, cell cycle analysis, conditioned medium western blot Journal of cellular biochemistry Medium 17340618
2008 CCN2 and CCN3 directly bind each other with a dissociation constant of 1.95 × 10⁻⁹ M (CCN2–CCN3) as determined by surface plasmon resonance; co-immunoprecipitation confirmed CCN2–CCN3 interaction in vitro and in vivo; GFP–CCN2 and Halo–CCN3 co-localize in COS7 cells; CCN3 inhibits CCN2-induced aggrecan and col2a1 expression in chondrocytes, and combined CCN2+CCN3 treatment abolishes CCN3's inhibitory effect. Yeast two-hybrid, co-immunoprecipitation, surface plasmon resonance (Kd measurement), fluorescent protein co-localization, chondrocyte gene expression assays The FEBS journal High 22812570
2008 CCN3 inhibits osteogenic differentiation via two pathways: (1) suppression of BMP signaling and (2) stimulation of Notch signaling; the CT domain is required for Notch activation and its anti-proliferative effect; anti-osteogenic activity is not completely abolished by CT domain deletion, suggesting a BMP pathway component independent of Notch. CCN3 and CT-deletion construct transfection into Kusa-A1 mesenchymal stem cells, adenoviral BMP-2 co-transduction, Notch target gene expression analysis Biochemical and biophysical research communications Medium 18275847
2009 CCN3 overexpression in breast cancer cells activates the small GTPase Rac1, induces formation of actin-enriched pseudopodia containing CCN3 and vinculin, and reduces cell growth; extracellular CCN3 is internalized to early endosomes; CCN3 associates with the cytoplasmic tail of Connexin43 (Cx43) intracellularly; Cx43 channel properties and protein levels are not affected by CCN3, but CCN3 is down-regulated in the absence of Cx43. Overexpression, exogenous protein treatment, Rac1 activity assay, endosome internalization assay, Co-IP with Cx43 The Journal of biological chemistry Medium 19706598
2010 CCN3 inhibits NF-κB nuclear translocation and its binding to the VCAM-1 promoter, reducing cytokine-induced VCAM-1 expression and monocyte adhesion in endothelial cells; CCN3 expression in HUVECs is transcriptionally induced by laminar shear stress and statins via KLF2. Adenoviral overexpression, CCN3 siRNA knockdown, NF-κB nuclear translocation assay, VCAM-1 promoter binding assay, KLF2 promoter analysis Journal of cell communication and signaling Medium 21063504
2010 CCN3 suppresses vascular smooth muscle cell proliferation by up-regulating CDK inhibitors p21 and p15 through a Notch signaling-dependent mechanism (γ-secretase inhibitor partially blocks p21 induction); CCN3 also inhibits VSMC migration; CCN3 knockout mice show 6-fold enhancement of neointimal thickening after endothelial injury. Recombinant CCN3 treatment of rat VSMC, neutralizing antibody, γ-secretase inhibitor, CCN3 knockout mice with photochemical injury model, histopathology Arteriosclerosis, thrombosis, and vascular biology High 20139355
2010 NOV/CCN3 upregulates CCL2 and CXCL1 expression in astrocytes through β1 integrin (for CCL2) and β5 integrin (for CXCL1), activating Rho/ROCK/JNK/NF-κB and Rho/ROCK/p38/NF-κB pathways, respectively; endogenous NOV controls basal chemokine synthesis; NOV intracerebral injection increases CCL2 and CXCL1 brain levels in vivo. Recombinant CCN3 treatment, siRNA knockdown of integrins β1 and β5, kinase inhibitors, ELISA, RT-qPCR, in vivo intracranial injection Glia Medium 20648642
2011 CCN3 promotes osteoclast differentiation from RANKL-primed monocyte precursors by promoting calcium oscillations and NFATc1 nuclear translocation; CCN3 inhibits osteoblast differentiation, raising the RANKL/OPG ratio; CCN3-overexpressing breast cancer cells show enhanced bone colonization in xenograft models. Recombinant CCN3 treatment of primary bone marrow cultures, calcium oscillation imaging, NFATc1 nuclear translocation assay, osteoblast/osteoclast differentiation assays, in vivo xenograft The American journal of pathology Medium 21514448
2012 CCN3 increases cell migration and ICAM-1 expression in prostate cancer cells through a pathway involving αvβ3 integrin, integrin-linked kinase (ILK), Akt, and NF-κB; CCN3 increases p65 binding to the NF-κB element in the ICAM-1 promoter. Recombinant CCN3 treatment, integrin-blocking antibodies, kinase inhibitors, NF-κB luciferase reporter, ChIP for p65 on ICAM-1 promoter, CCN3 knockdown in vivo bone metastasis Carcinogenesis Medium 22345292
2012 CCN3 increases migration and MMP-13 expression in human chondrosarcoma cells through αvβ3/αvβ5 integrins, FAK, PI3K, Akt, p65, and NF-κB; CCN3 increases NF-κB luciferase activity and p65 binding to the MMP-13 promoter. Integrin-blocking antibodies, kinase inhibitors, NF-κB reporter, ChIP, CCN3 recombinant protein treatment Journal of cellular physiology Medium 21344378
2011 CCN3 overexpression in melanoma cells induces increased expression of integrins α7β1 and αvβ5 (at mRNA level) and increased adhesion to laminin and vitronectin; secreted CCN3 acts as an adhesion matrix for melanoma cells; CCN3 siRNA decreases adhesion to laminin and vitronectin. CCN3 overexpression, siRNA knockdown, integrin mRNA analysis, adhesion assays, in vivo xenograft Cancer research Medium 18245471
2006 In CML cells, BCR-ABL kinase activity down-regulates intracellular CCN3 protein while promoting its secretion (tyrosine-phosphorylated form detected); imatinib or BCR-ABL siRNA increases CCN3 expression; CCN3 transfection into BCR-ABL+ cells inhibits proliferation and decreases clonogenicity. Northern and Western blotting, immunocytochemistry, imatinib treatment, BCR-ABL siRNA, CCN3 transfection, colony assays Blood Medium 16670264
2014 Nov/CCN3 maintains long-term repopulating activity of murine HSCs via association with integrin αvβ3; TPO is required for Nov binding to integrin αvβ3 and stimulates Nov expression in HSCs; IFNγ suppresses TPO-induced Nov expression and impairs LTR activity. Integrin αvβ3 binding assay, competitive transplantation assays, cytokine treatment, gene expression analysis International journal of hematology Medium 24563081
2016 CCN3 mitigates abdominal aortic aneurysm in mice; CCN3-deficient mice develop severe AAA upon angiotensin II or elastase exposure; CCN3 overexpression reduces AAA formation; bone marrow transplant experiments show the AAA phenotype is intrinsic to the vasculature (not BM-derived); ERK1/2 pathway is identified as a critical mediator of CCN3-dependent AAA. Germline Ccn3 knockout mice, transgenic CCN3 overexpression, bone marrow transplantation, pharmacological ERK1/2 inhibition, rodent AAA models The Journal of clinical investigation High 26974158
2016 CCN3 deficiency in bone marrow-derived macrophages leads to increased lipid uptake and foam cell formation, attributable to increased expression of scavenger receptors CD36 and SRA1; BM transplantation showed CCN3 deficiency specifically in bone marrow drives increased atherosclerotic plaque burden. Bone marrow transplantation experiments, isolated peritoneal macrophage lipid uptake assays, scavenger receptor gene expression analysis The American journal of pathology Medium 28527710
2012 NOV/CCN3 attenuates inflammatory pain by inhibiting TNF-α-induced MMP-9 expression in DRG neurons through β1 integrin engagement; intrathecal CCN3 siRNA upregulates MMP-9 in DRG and MMP-2 in DHSC with increased mechanical allodynia; intrathecal CCN3 protein abolishes MMP-9 induction and reduces allodynia. Cultured DRG neurons with siRNA and recombinant CCN3, integrin β1 blocking, in vivo CFA pain model with intrathecal delivery, zymography for MMP activity Journal of neuroinflammation Medium 22353423
2013 CCN3 is a transcriptional target of FoxO1 in pancreatic β-cells; FoxO1 binds to an evolutionarily conserved response element in the Ccn3 promoter; CCN3 impairs β-cell proliferation (concurrent with reduced cAMP levels), decreases glucose oxidation, and inhibits glucose-stimulated Ca2+ entry and insulin secretion. Promoter-binding (FoxO1 ChIP/reporter), FoxO1 constitutively active overexpression, CCN3 functional assays in β-cells (cAMP measurement, Ca2+ entry, glucose oxidation, insulin secretion) PloS one Medium 23705021
2017 The VWC domain of CCN3 was crystallized by X-ray crystallography; structural analysis showed the CCN3 VWC domain N-terminal fold differs substantially from that of crossveinless-2 VWC; no direct binding between CCN3 VWC domain and BMP-2 was detected in this study. X-ray crystallography, direct BMP-2 binding assays The Journal of biological chemistry High 28584056
2016 MMP14 (MT1-MMP) and MMP2 cleave CCN3 in the variable region; additional cleavage by MMP1, MMP8, and MMP9 was also demonstrated; these substrates were identified by inactive-catalytic-domain capture yeast two-hybrid trapping and validated biochemically in vitro. MMP14 inactive catalytic domain yeast two-hybrid substrate trapping, degradomics mass spectrometry, in vitro biochemical MMP cleavage assays Matrix biology High 27471094
2010 CCN3 interacts with Connexin43 at the C-terminus (FRET confirmed interaction with Cx43 truncations ending at aa 374, 273, 264, and 257); only wild-type Cx43 and the 1–374 deletion mutant interaction with CCN3 led to increased CCN3 expression and reduced cell proliferation, indicating that specific binding geometry controls downstream signaling. FRET, co-immunoprecipitation, cell proliferation assays, Cx43 C-terminal deletion mutants Journal of cellular biochemistry Medium 20336664
2016 Periostin interacts with CCN3; immunoprecipitation revealed that the TSP1-CT domains of CCN3 interact with the 4 FAS1 repeat domains of periostin; targeted disruption of the periostin gene in mice decreased the matricellular localization of CCN3 in the periodontal ligament. Co-immunoprecipitation, immunofluorescence co-localization, periostin knockout mouse model Journal of cell communication and signaling Medium 28013443
2013 CCN3 induces osteoclastogenesis through the RANKL-dependent pathway in prostate cancer bone metastasis; CCN3 activates the FAK/Akt/p38/NF-κB signaling pathway to increase RANKL expression in osteoblasts; treatment of osteoblasts with CCN3 shifts the RANKL/OPG ratio toward osteoclastogenesis. Neutralizing antibody against CCN3, kinase inhibitors, osteoclast differentiation assays, in vivo bone metastasis model Carcinogenesis Medium 23536580
2013 In CCN3 knockout mice, bone regeneration is accelerated with earlier upregulation of osteoblast-related genes; Smad1/5 phosphorylation is highly upregulated at bone regeneration sites in CCN3 KO mice; CCN3 transgenic mice (Col1a1-driven) show osteopenia. CCN3 knockout mice, CCN3 transgenic mice, micro-CT, histological analysis, RT-PCR for osteogenic markers, Smad1/5 phosphorylation western blot The Journal of biological chemistry Medium 23653360
2013 CCN3 in CML cells reduces NOTCH1 intracellular domain (NOTCH1-ICD) cleavage by >50% and decreases c-MYC and HES1 expression; BCR-ABL silencing reduces NOTCH1-FL and NOTCH1-ICD; CCN3 acts as a non-canonical NOTCH1 ligand to reduce NOTCH1 signaling in CML. BCR-ABL siRNA silencing, stable CCN3 overexpression (K562/CCN3), recombinant CCN3 treatment, gamma-secretase inhibitor, NOTCH1-ICD western blot The Journal of pathology Medium 24308033
2011 In CML, BCR-ABL upregulates miR-130a and miR-130b, which directly target CCN3 mRNA and reduce both CCN3 mRNA and protein; transfection of mature miR-130a or miR-130b individually into BCR-ABL negative HL60 cells decreases CCN3 expression. BCR-ABL siRNA, Taqman miRNA array, miR-130a/130b transfection in HL60 cells, CCN3 mRNA and protein measurement Journal of cell communication and signaling Medium 21638198
2019 CCN3 promotes the expression of Runx2 and osterix in osteoblasts by inhibiting miR-608 expression via FAK and Akt signaling pathways. CCN3 recombinant protein treatment, FAK/Akt inhibitors, miR-608 expression analysis, Alizarin red-S and ALP staining for osteoblast differentiation International journal of molecular sciences Medium 31284378
2009 NOV/CCN3 reduces Sonic Hedgehog-induced granule neuron precursor (GNP) proliferation in the cerebellum through β3 integrins and stimulation of GSK3-β activity; NOV stimulates GNP migration through RGD-dependent integrins distinct from those mediating proliferation suppression. Recombinant NOV treatment, integrin-blocking antibodies (β3 and RGD-sensitive), GSK3-β activity assay, proliferation and migration assays in GNP cultures Molecular and cellular neurosciences Medium 19286457
2012 Non-glycosylated CCN3 (ng-CCN3) promotes Jeg3 trophoblast migration through Akt and integrin α5β1, while both glycosylated and non-glycosylated forms reduce proliferation via Notch/p21; antiproliferative signaling uses Notch1/p21 pathway while pro-migratory signaling requires Akt and α5β1 integrin. Stable transfection with full-length CCN3, recombinant glycosylated/non-glycosylated CCN3 treatment, Akt/MAPK/Notch inhibitors, integrin α5β1 blocking antibodies Molecular human reproduction Medium 23220688
2017 TGFβ1 suppresses CCN3 mRNA expression in human dermal fibroblasts via ALK5 in a pathway insensitive to FAK, MEK, TAK1, or YAP1 inhibition, in contrast to CCN1 and CCN2 induction which requires FAK and MEK. TGFβ1 treatment, signal transduction inhibitors (ALK5, FAK, MEK, TAK1, YAP1), mRNA quantification by RT-qPCR and western blot PloS one Medium 31170244
2023 CCN3 promotes TNBC metastasis by inducing GPNMB expression, which activates the EGFR/MAPK pathway; CCN3 activates Wnt signaling to increase MITF protein, a transcription factor driving GPNMB expression. CCN3 knockdown, transcriptome profiling, GPNMB expression analysis, EGFR/MAPK pathway western blot, Wnt signaling assays, TCGA dataset analysis Cell death & disease Medium 36737605
2019 CCN3 inhibits IL-1β-induced matrix catabolism in chondrocytes, promotes autophagy (increased Atg5, Beclin1, LC3-II), decreases HMGB1 expression, and attenuates activation of the PI3K/AKT/mTOR pathway. Recombinant CCN3 and CCN3 overexpression in chondrocytes, IL-1β treatment, western blot for autophagy markers and PI3K/AKT/mTOR, HMGB1 analysis Journal of cellular and molecular medicine Medium 31454155
2017 CCN3 promotes EMT in prostate cancer cells by activating the FAK/Akt/HIF-1α pathway, leading to Twist expression; CCN3 overexpression or knockdown alters EMT phenotype; recombinant CCN3 promotes EMT. CCN3 overexpression and knockdown, recombinant CCN3 treatment, FAK/Akt/HIF-1α western blot, Twist expression analysis, orthotopic in vivo metastasis model, IHC Oncotarget Medium 29088803

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. The Journal of biological chemistry 172 12695522
2002 The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. The Journal of biological chemistry 172 12050162
2004 CCN3 (NOV) interacts with connexin43 in C6 glioma cells: possible mechanism of connexin-mediated growth suppression. The Journal of biological chemistry 135 15213231
2004 Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing. The Journal of biological chemistry 112 15611078
2002 The expression of ccn3(nov) gene in musculoskeletal tumors. The American journal of pathology 99 11891184
2009 CCN3 (NOV) is a negative regulator of CCN2 (CTGF) and a novel endogenous inhibitor of the fibrotic pathway in an in vitro model of renal disease. The American journal of pathology 97 19359517
2008 Cooperative regulation of chondrocyte differentiation by CCN2 and CCN3 shown by a comprehensive analysis of the CCN family proteins in cartilage. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 95 18597638
2007 NOV (CCN3) functions as a regulator of human hematopoietic stem or progenitor cells. Science (New York, N.Y.) 94 17463287
2007 CCN3/NOV inhibits BMP-2-induced osteoblast differentiation by interacting with BMP and Notch signaling pathways. Biochemical and biophysical research communications 87 17250806
2006 CCN3 controls 3D spatial localization of melanocytes in the human skin through DDR1. The Journal of cell biology 86 17101694
2001 Inhibition of glioma cell growth and tumorigenic potential by CCN3 (NOV). Molecular pathology : MP 86 11577170
2017 Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development. International journal of molecular sciences 85 28809783
2005 In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type. Oncogene 84 15824736
2010 CCN3 inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration. Arteriosclerosis, thrombosis, and vascular biology 78 20139355
2008 Abnormal skeletal and cardiac development, cardiomyopathy, muscle atrophy and cataracts in mice with a targeted disruption of the Nov (Ccn3) gene. BMC developmental biology 76 18289368
2010 A novel role of CCN3 in regulating endothelial inflammation. Journal of cell communication and signaling 64 21063504
2001 Differential expression of the ccn3 (nov) proto-oncogene in human prostate cell lines and tissues. Molecular pathology : MP 62 11477145
2006 Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associated with pre-eclampsia. Molecular human reproduction 61 16675545
2001 The expression of ccn3 (nov) RNA and protein in the rat central nervous system is developmentally regulated. Molecular pathology : MP 58 11376133
2016 NOV/CCN3: A New Adipocytokine Involved in Obesity-Associated Insulin Resistance. Diabetes 57 27284105
2011 MicroRNAs 130a/b are regulated by BCR-ABL and downregulate expression of CCN3 in CML. Journal of cell communication and signaling 57 21638198
2007 Antiproliferative activity of CCN3: involvement of the C-terminal module and post-translational regulation. Journal of cellular biochemistry 57 17340618
2007 Downregulation of CCN3 expression as a potential mechanism for melanoma progression. Oncogene 57 17968313
2008 CCN3/nephroblastoma overexpressed matricellular protein regulates integrin expression, adhesion, and dissemination in melanoma. Cancer research 55 18245471
2003 NOV (CCN3) regulation in the growth plate and CCN family member expression in cartilage neoplasia. The Journal of pathology 55 14648665
2006 Nuclear addressing provides a clue for the transforming activity of amino-truncated CCN3 proteins. Journal of cellular biochemistry 54 16598765
2013 CCN3 protein participates in bone regeneration as an inhibitory factor. The Journal of biological chemistry 53 23653360
2007 Nephroblastoma overexpressed/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 (NOV/CCN3), a selective adrenocortical cell proapoptotic factor, is down-regulated in childhood adrenocortical tumors. The Journal of clinical endocrinology and metabolism 53 17566092
2006 A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation. Blood 53 16670264
2016 Matricellular protein CCN3 mitigates abdominal aortic aneurysm. The Journal of clinical investigation 47 26974158
2010 Regulation of the matricellular proteins CYR61 (CCN1) and NOV (CCN3) by hypoxia-inducible factor-1{alpha} and transforming-growth factor-{beta}3 in the human trophoblast. Endocrinology 47 20237132
2013 Plasma NOV/CCN3 levels are closely associated with obesity in patients with metabolic disorders. PloS one 46 23785511
2010 NOV/CCN3 upregulates CCL2 and CXCL1 expression in astrocytes through beta1 and beta5 integrins. Glia 46 20648642
2014 hsa-mir-30c promotes the invasive phenotype of metastatic breast cancer cells by targeting NOV/CCN3. Cancer cell international 45 25120384
2012 CCN3 increases BMP-4 expression and bone mineralization in osteoblasts. Journal of cellular physiology 45 21898398
2011 CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone. The American journal of pathology 45 21514448
2010 CCN3/CCN2 regulation and the fibrosis of diabetic renal disease. Journal of cell communication and signaling 45 20195391
2008 Dose-dependent differential upregulation of CCN1/Cyr61 and CCN3/NOV by the gap junction protein Connexin43 in glioma cells. Journal of cellular biochemistry 45 18004727
2012 CCN3 increases cell motility and ICAM-1 expression in prostate cancer cells. Carcinogenesis 43 22345292
2007 CCN3 is a novel endogenous PDGF-regulated inhibitor of glomerular cell proliferation. Kidney international 43 17914348
2002 A role for CCN3 (NOV) in calcium signalling. Molecular pathology : MP 43 12147716
2013 CCN3 promotes prostate cancer bone metastasis by modulating the tumor-bone microenvironment through RANKL-dependent pathway. Carcinogenesis 42 23536580
2019 NOV/CCN3 induces cartilage protection by inhibiting PI3K/AKT/mTOR pathway. Journal of cellular and molecular medicine 41 31454155
2011 CCN3 increases cell motility and MMP-13 expression in human chondrosarcoma through integrin-dependent pathway. Journal of cellular physiology 41 21344378
2010 Antagonistic effect of the matricellular signaling protein CCN3 on TGF-beta- and Wnt-mediated fibrillinogenesis in systemic sclerosis and Marfan syndrome. The Journal of investigative dermatology 41 20182440
2012 Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. Experimental dermatology 38 22507556
2004 Potential cellular conformations of the CCN3(NOV) protein. Cell communication and signaling : CCS 37 15361251
2012 Roles of heterotypic CCN2/CTGF-CCN3/NOV and homotypic CCN2-CCN2 interactions in expression of the differentiated phenotype of chondrocytes. The FEBS journal 35 22812570
2008 Inhibitory effect of CT domain of CCN3/NOV on proliferation and differentiation of osteogenic mesenchymal stem cells, Kusa-A1. Biochemical and biophysical research communications 35 18275847
2019 CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts. International journal of molecular sciences 34 31284378
2009 Matricellular protein CCN3 (NOV) regulates actin cytoskeleton reorganization. The Journal of biological chemistry 33 19706598
2008 CCN3--a key regulator of the hematopoietic compartment. Blood reviews 33 18752874
2014 Treatment with the matricellular protein CCN3 blocks and/or reverses fibrosis development in obesity with diabetic nephropathy. The American journal of pathology 32 25193594
2012 CCN3 regulates proliferation and migration properties in Jeg3 trophoblast cells via ERK1/2, Akt and Notch signalling. Molecular human reproduction 32 23220688
2005 New target genes for NOV/CCN3 in chondrocytes: TGF-beta2 and type X collagen. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32 16294274
2016 Degradomic and yeast 2-hybrid inactive catalytic domain substrate trapping identifies new membrane-type 1 matrix metalloproteinase (MMP14) substrates: CCN3 (Nov) and CCN5 (WISP2). Matrix biology : journal of the International Society for Matrix Biology 31 27471094
2006 New insight into CCN3 interactions--nuclear CCN3 : fact or fantasy? Cell communication and signaling : CCS 31 16895594
2007 The circulating proangiogenic factors CYR61 (CCN1) and NOV (CCN3) are significantly decreased in placentae and sera of preeclamptic patients. Reproductive sciences (Thousand Oaks, Calif.) 30 18089610
2017 Structural analyses of von Willebrand factor C domains of collagen 2A and CCN3 reveal an alternative mode of binding to bone morphogenetic protein-2. The Journal of biological chemistry 29 28584056
2015 Reduced NOV/CCN3 Expression Limits Inflammation and Interstitial Renal Fibrosis after Obstructive Nephropathy in Mice. PloS one 29 26367310
2006 NOV/CCN3 impairs muscle cell commitment and differentiation. Experimental cell research 29 16600215
2014 Promotion of dentin regeneration via CCN3 modulation on Notch and BMP signaling pathways. Biomaterials 28 24406215
2020 CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage. International journal of molecular sciences 27 33066270
2019 Yin/Yang expression of CCN family members: Transforming growth factor beta 1, via ALK5/FAK/MEK, induces CCN1 and CCN2, yet suppresses CCN3, expression in human dermal fibroblasts. PloS one 27 31170244
2018 CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner. Cell death & disease 27 30538222
2016 CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties. Cell adhesion & migration 27 26744771
2014 Nov/CCN3 regulates long-term repopulating activity of murine hematopoietic stem cells via integrin αvβ3. International journal of hematology 27 24563081
2012 NOV/CCN3 attenuates inflammatory pain through regulation of matrix metalloproteinases-2 and -9. Journal of neuroinflammation 27 22353423
2005 NOV/CCN3 induces adhesion of muscle skeletal cells and cooperates with FGF2 and IGF-1 to promote proliferation and survival. Cell communication & adhesion 27 16371345
2003 CCN3 and calcium signaling. Cell communication and signaling : CCS 27 14606958
2017 CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis. The American journal of pathology 25 28527710
2014 Overexpression of CCN3 inhibits inflammation and progression of atherosclerosis in apolipoprotein E-deficient mice. PloS one 25 24722330
2013 Nov/Ccn3, a novel transcriptional target of FoxO1, impairs pancreatic β-cell function. PloS one 25 23705021
2011 Impact of CCN3 (NOV) glycosylation on migration/invasion properties and cell growth of the choriocarcinoma cell line Jeg3. Human reproduction (Oxford, England) 25 21784733
2009 NOV/CCN3 promotes maturation of cerebellar granule neuron precursors. Molecular and cellular neurosciences 25 19286457
2017 CCN3 suppresses TGF-β1-induced extracellular matrix accumulation in human mesangial cells in vitro. Acta pharmacologica Sinica 24 28858296
2012 A novel, dual role of CCN3 in experimental glomerulonephritis: pro-angiogenic and antimesangioproliferative effects. The American journal of pathology 24 22538190
2011 Novel effects of CCN3 that may direct the differentiation of chondrocytes. FEBS letters 24 21871891
2023 CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer. Cell death & disease 23 36737605
2020 Dynamic CCN3 expression in the murine CNS does not confer essential roles in myelination or remyelination. Proceedings of the National Academy of Sciences of the United States of America 23 32651278
2007 Domain-specific CCN3 antibodies as unique tools for structural and functional studies. Journal of cell communication and signaling 23 18481200
2012 Adenoviral CCN3/NOV gene transfer fails to mitigate liver fibrosis in an experimental bile duct ligation model because of hepatocyte apoptosis. Liver international : official journal of the International Association for the Study of the Liver 22 22698069
2006 The CCN3 protein and cancer. Advances in experimental medicine and biology 22 17163153
2021 The Emerging Roles of CCN3 Protein in Immune-Related Diseases. Mediators of inflammation 21 34393649
2016 Novel role of CCN3 that maintains the differentiated phenotype of articular cartilage. Journal of bone and mineral metabolism 21 27853940
2015 Yin and Yang revisited: CCN3 as an anti-fibrotic therapeutic? Journal of cell communication and signaling 21 25700690
2011 Transforming growth factor β controls CCN3 expression in nucleus pulposus cells of the intervertebral disc. Arthritis and rheumatism 21 21618206
2017 CCN3 promotes epithelial-mesenchymal transition in prostate cancer via FAK/Akt/HIF-1α-induced twist expression. Oncotarget 20 29088803
2016 Periostin is required for matricellular localization of CCN3 in periodontal ligament of mice. Journal of cell communication and signaling 20 28013443
2009 CCN3: a key growth regulator in Chronic Myeloid Leukaemia. Journal of cell communication and signaling 20 19623482
2007 Expression of CCN3 protein in human Wilms' tumors: immunohistochemical detection of CCN3 variants using domain-specific antibodies. Virchows Archiv : an international journal of pathology 20 18066593
2003 The CCN3 (NOV) cell growth regulator: a new tool for molecular medicine. Expert review of molecular diagnostics 20 14510180
2019 Regulatory mechanism of NOV/CCN3 in the inflammation and apoptosis of lung epithelial alveolar cells upon lipopolysaccharide stimulation. Molecular medicine reports 19 31545412
2013 The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia. The Journal of pathology 19 24308033
2010 More insights into the CCN3/Connexin43 interaction complex and its role for signaling. Journal of cellular biochemistry 19 20336664
2022 Molecular and Genetic Interactions between CCN2 and CCN3 behind Their Yin-Yang Collaboration. International journal of molecular sciences 18 35682564
2020 Nov/CCN3 Enhances Cord Blood Engraftment by Rapidly Recruiting Latent Human Stem Cell Activity. Cell stem cell 18 32197066
2014 Targeted mutation of NOV/CCN3 in mice disrupts joint homeostasis and causes osteoarthritis-like disease. Osteoarthritis and cartilage 18 25541297
2009 CCN3 and bone marrow cells. Journal of cell communication and signaling 18 19626464
2020 CCN3 Signaling Is Differently Regulated in Placental Diseases Preeclampsia and Abnormally Invasive Placenta. Frontiers in endocrinology 17 33304321

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