Affinage

CCN1

CCN family member 1 · UniProt O00622

Length
381 aa
Mass
42.0 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 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

CCN1 (CYR61) is a secreted, heparin- and ECM-associated matricellular protein, first identified as a serum/PDGF-inducible immediate-early gene product that associates strongly with the extracellular matrix rather than diffusing freely, and is internalized and degraded via the lysosome (PMID:2355916, PMID:9184077). It functions principally as a multivalent integrin ligand whose biological output is dictated by the receptor and cell-type context. Through αvβ3/αvβ5 it supports survival, adhesion, and angiogenesis—its genetic deletion causes embryonic lethality from failed chorioallantoic fusion and placental vascular insufficiency (PMID:12446788), and it amplifies endothelial tip-cell activity by coupling VEGFR2 to αvβ3 (PMID:31429823). Through integrin α6β1 together with the heparan sulfate proteoglycan syndecan-4, CCN1 instead drives transcription-independent p53-dependent apoptosis in fibroblasts (PMID:16275757) and RAC1-NOX1 ROS-dependent senescence via the p16INK4a/pRb pathway, with a senescence-defective knockin allele producing exacerbated fibrosis (PMID:20526329). In innate immunity, CCN1 engages αMβ2/syndecan-4 on macrophages to directly activate NF-κB and a proinflammatory program (PMID:20164416), serves as a phosphatidylserine-bridging opsonin for neutrophil efferocytosis via αvβ3/αvβ5 (PMID:26077348), and acts as a pattern-recognition molecule binding bacterial PAMPs and directly engaging TLR2/TLR4 to trigger MyD88-dependent signaling (PMID:32144270). CCN1 expression is itself an integrating node of mechanotransduction and growth-factor signaling, induced by RhoA/MRTF-A (PMID:25106095), YAP/TEAD (PMID:31262999, PMID:38521502), and TGF-β/Smad (PMID:38521502), and its secretion and cell-surface display require O-fucosylation at Thr242 by POFUT2 (PMID:26424659). Across intestinal stem cells (PMID:35660741), bone (PMID:29351359), liver (PMID:26028023, PMID:37756381), and vasculature (PMID:30917686), CCN1 coordinates NF-κB/Notch, Src/YAP/Wnt, and integrin-α6β1/NF-κB feedback circuits to balance proliferation, differentiation, inflammation, and tissue repair.

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1990 Medium

    Established the molecular identity and regulation of CCN1 as a secreted cysteine-rich immediate-early gene product, framing it as a candidate growth-factor-responsive signaling molecule.

    Evidence Northern blot, immunoprecipitation, cell-cycle and PKC-pathway inhibition in cultured cells

    PMID:2355916

    Open questions at the time
    • No receptor or downstream signaling identified
    • Function of the secreted protein not defined
  2. 1997 High

    Defined CCN1 as an ECM-associated, heparin-binding ligand acting on cell-surface receptors to promote adhesion, migration, and proliferation, moving it from a transcript to a functional matricellular protein.

    Evidence Purified recombinant protein in heparin-binding, adhesion/migration/proliferation, and lysosomal-degradation assays across multiple cell types

    PMID:9184077

    Open questions at the time
    • Specific receptors not yet identified
    • Mechanism of cell-type-specific responses unknown
  3. 2002 High

    Demonstrated an essential, non-redundant in vivo role in vascular development, establishing CCN1 as required for placental angiogenesis and viability.

    Evidence Cyr61 knockout mouse with histology and Vegf-C expression analysis

    PMID:12446788

    Open questions at the time
    • Receptor mediating the angiogenic effect not defined
    • Relationship between vascular and other functions unclear
  4. 2005 High

    Resolved how CCN1 can be proapoptotic by identifying α6β1/syndecan-4 engagement that triggers transcription-independent p53/Bax-mediated apoptosis, explaining cell-type-specific opposing outcomes.

    Evidence Receptor-blocking antibodies, siRNA, caspase and cytochrome c assays in fibroblasts versus endothelial cells

    PMID:15961723 PMID:16275757

    Open questions at the time
    • How receptor context switches survival versus death not fully resolved
    • In vivo relevance not yet tested at this stage
  5. 2010 High

    Connected CCN1 to senescence and inflammation by defining the α6β1-RAC1-NOX1-ROS-p16/pRb senescence axis and the αMβ2/syndecan-4-NF-κB macrophage program, with an in vivo antifibrotic role.

    Evidence Senescence-defective knockin mice, ROS and RAC1-NOX1 assays, macrophage NF-κB reporters and receptor blocking

    PMID:20164416 PMID:20526329

    Open questions at the time
    • Structural basis of distinct integrin engagement unresolved
    • How ROS levels are tuned for senescence versus apoptosis unclear
  6. 2013 High

    Placed CCN1 within upstream signaling cascades, showing LPA1-induced CCN1 bridges to α6β1/αvβ3-FAK to drive smooth muscle migration and that RhoA/MRTF-A induction yields autocrine cardioprotection.

    Evidence LPA1 knockout cells, RhoA/MRTF-A inhibition, cardiac-specific CCN1 KO and I/R injury models

    PMID:24371135 PMID:25106095

    Open questions at the time
    • Tissue-specific determinants of protective versus damaging output unclear
  7. 2015 High

    Expanded CCN1 into innate immune clearance and biosynthetic regulation: it bridges phosphatidylserine to αvβ3/αvβ5 for efferocytosis, requires POFUT2 O-fucosylation at Thr242 for secretion, and directly inhibits ADAMTS-4 aggrecanase.

    Evidence Knockin/knockdown efferocytosis mice, mass spectrometry plus Thr242 mutagenesis, co-IP and aggrecan digestion assays

    PMID:25709087 PMID:25807183 PMID:26028023 PMID:26077348 PMID:26424659

    Open questions at the time
    • Whether O-fucosylation modulates receptor selectivity not tested
    • Range of direct protein partners beyond ADAMTS-4 unexplored
  8. 2019 High

    Defined CCN1 as a mechanotransduction node embedded in feedback loops: shear-induced α6β1/NF-κB promotes atherosclerosis, while YAP directly targets CCN1, which in turn restrains YAP through matrix compliance, and CCN1 couples VEGFR2-αvβ3 for sprouting.

    Evidence Knockin atherosclerosis mice, YAP ChIP on CCN1 promoter, EC-specific KO, zebrafish/mouse angiogenesis and VEGFR2 co-IP

    PMID:30917686 PMID:31262999 PMID:31429823

    Open questions at the time
    • How opposing positive and negative feedback loops are balanced in vivo unclear
  9. 2020 High

    Established CCN1 as a bona fide pattern-recognition molecule binding bacterial PAMPs and directly engaging TLR2/TLR4 to drive MyD88-dependent antimicrobial responses.

    Evidence PAMP and TLR binding assays, phagocytosis assays, myeloid-specific KO and binding-defective knockin mice in infection models

    PMID:32144270

    Open questions at the time
    • Structural basis of direct TLR binding not defined
    • Relationship between TLR and integrin engagement unresolved
  10. 2022 High

    Defined a tissue-homeostatic role in intestinal stem cells, showing CCN1 partitions αvβ3/αvβ5 signaling into NF-κB/Jag1-Notch differentiation and Src/YAP/Wnt proliferation arms in a reciprocal loop with YAP.

    Evidence Lgr5+ ISC Ccn1 deletion, binding-defective knockin mice, crypt organoids with Notch/YAP/Wnt readouts

    PMID:35660741

    Open questions at the time
    • How a single ligand bifurcates into distinct downstream programs mechanistically unclear
  11. 2025 High

    Revealed an unexpected intracellular function: during ferroptosis CCN1 relocates to mitochondrial complexes to facilitate ETFA-dependent fatty acid β-oxidation, fueling ROS and lipid peroxidation distinct from the canonical CPT2-ETFA route.

    Evidence Multiomics screening, subcellular fractionation/co-IP with mitochondrial complexes, β-oxidation and lipid peroxidation assays, KO cells and mouse models

    PMID:40280135

    Open questions at the time
    • Mechanism of CCN1 trafficking from ECM to mitochondria unknown
    • How a secreted protein accesses the mitochondrial matrix unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single matricellular ligand's structural features dictate the choice among integrin/co-receptor partners and thereby switch between survival, apoptosis, senescence, inflammation, and intracellular metabolic roles.
  • No structural model of CCN1-receptor complexes
  • Determinants of cell-type-specific output not defined
  • Trafficking routes between ECM, surface, and organelles incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 7 GO:0048018 receptor ligand activity 5 GO:0008289 lipid binding 1 GO:0060089 molecular transducer activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 3 GO:0005739 mitochondrion 1 GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1430728 Metabolism 1
Partners
ETFAITGA6ITGAVITGB1ITGB3SDC4TLR2TLR4

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 CYR61/CCN1 encodes a 379-amino-acid cysteine-rich polypeptide with an N-terminal secretory signal sequence; its mRNA is induced by serum/PDGF as an immediate-early gene through both protein kinase C-dependent and -independent pathways, accumulates from G0/G1 transition through mid-G1, and the protein has a short intracellular half-life. Northern blot, immunoprecipitation, cell cycle analysis, pharmacological pathway inhibition Molecular and cellular biology Medium 2355916
1997 CYR61/CCN1 is an extracellular matrix-associated signaling molecule; it binds heparin with higher affinity than FISP12/CTGF, associates strongly with the ECM (not secreted freely into medium), is internalized and degraded via the lysosomal pathway after interacting with cell surface receptors, and promotes cell proliferation, migration, and adhesion in fibroblasts, endothelial, and epithelial cells. Protein purification, heparin-binding assay, cell adhesion/migration/proliferation assays, lysosomal inhibitor experiments, immunohistochemistry Experimental cell research High 9184077
2002 Genetic deletion of Cyr61 in mice causes embryonic lethality due to failure of chorioallantoic fusion and placental vascular insufficiency; CCN1 is required for vessel bifurcation (non-sprouting angiogenesis) at the chorioallantoic junction and regulates Vegf-C expression in allantoic mesoderm. Gene knockout mouse, histology, immunohistochemistry, molecular analysis of Vegf-C expression Molecular and cellular biology High 12446788
2003 Xenopus Cyr61 is required for normal gastrulation movements; it acts through its adhesive properties to modulate extracellular matrix assembly and can stimulate or inhibit Wnt pathway signaling in a context-dependent manner. Gain- and loss-of-function experiments in Xenopus laevis embryos, extracellular matrix assembly assays, Wnt pathway reporter assays Development (Cambridge, England) High 12702657
2005 CCN1/CYR61 induces apoptosis in fibroblasts (but not endothelial cells) upon cell adhesion through integrin α6β1 and the heparan sulfate proteoglycan syndecan-4; this triggers transcription-independent p53 activation of Bax, cytochrome c release, and activation of caspase-9 and caspase-3, without requiring caspase-8 or de novo transcription/translation. Cell adhesion assay, integrin-blocking antibodies, siRNA knockdown of receptors, caspase activity assays, cytochrome c release, p53 activation assays, co-immunoprecipitation The Journal of cell biology High 16275757
2010 CCN1 induces fibroblast senescence by binding to integrin α6β1 and heparan sulfate proteoglycans, activating DNA damage response pathways and p53, and stimulating the RAC1-NOX1 complex to generate ROS; this leads to ROS-dependent activation of the p16INK4a/pRb pathway, causing senescence and antifibrotic gene expression. Knockin mice expressing a senescence-defective CCN1 mutant develop exacerbated fibrosis. Knockin mouse model, integrin-blocking antibodies, ROS measurement, RAC1-NOX1 complex analysis, p53/p16/pRb pathway analysis, gene expression profiling, topical protein application Nature cell biology High 20526329
2010 CCN1 supports macrophage adhesion through integrin αMβ2 and syndecan-4, directly activates NF-κB-mediated transcription, and induces a proinflammatory M1 macrophage genetic program via two mechanisms: an immediate-early NF-κB-dependent cytokine response and a delayed autocrine/paracrine TNF-α-mediated secondary cytokine response. Macrophage adhesion assay, NF-κB reporter assay, integrin-blocking antibodies, siRNA knockdown of syndecan-4, gene expression profiling, TNF-α neutralization Journal of immunology High 20164416
2013 LPA induces temporal and spatial expression of Cyr61/CCN1, which accumulates in the Golgi apparatus and translocates to the ECM; extracellular Cyr61 bridges LPA receptor 1 (LPA1) signaling to integrin α6β1 and αvβ3, which activate focal adhesion kinase (FAK), driving smooth muscle cell migration. LPA1 knockout cells lack Cyr61 induction and migration. siRNA knockdown, antibody blockade, LPA receptor knockout cells, subcellular fractionation/immunofluorescence, FAK phosphorylation assay, cell migration assay The Journal of biological chemistry High 24371135
2014 CCN1 in cardiomyocytes is induced by RhoA activation downstream of GPCR agonists (S1P, LPA, endothelin-1) through MRTF-A (MKL1)/SRF signaling; secreted CCN1 binds back to cardiomyocytes in an autocrine fashion and protects against ischemia/reperfusion injury. Cardiac-specific CCN1 KO mice show increased infarct size after I/R. RhoA inhibition (C3 exoenzyme, pharmacological), MRTF-A knockdown/inhibitors, siRNA knockdown of CCN1, simulated ischemia/reperfusion in NRVMs, cardiac-specific CCN1 KO mouse model, infarct size measurement Journal of molecular and cellular cardiology High 25106095
2015 CCN1 acts as a bridging molecule in neutrophil efferocytosis by binding phosphatidylserine on apoptotic neutrophils and integrins αvβ3/αvβ5 on macrophages; knockin mice with a CCN1 mutant unable to bind αvβ3/αvβ5 or Ccn1 knockdown mice exhibit defective neutrophil clearance, exuberant neutrophil accumulation, and delayed wound healing. Phosphatidylserine binding assay, integrin-binding assays, knockin mouse model, Ccn1 knockdown mice, efferocytosis assays, wound healing analysis in diabetic Lepr(db/db) mice Nature communications High 26077348
2015 CCN1 promotes mucosal healing in colitis by inducing IL-6 expression through integrin αMβ2 in macrophages and integrin α6β1 in fibroblasts; IL-6 in turn stimulates intestinal epithelial cell proliferation. Ccn1(dm/dm) knockin mice (αMβ2/α6β1-binding defective) show impaired healing and reduced IL-6 during DSS colitis recovery. Knockin mouse model (Ccn1 dm/dm), DSS colitis model, integrin-blocking antibodies, CCN1 protein administration, IL-6 delivery rescue, IEC proliferation assay Mucosal immunology High 25807183
2015 CCN1 suppresses hepatocarcinogenesis by inhibiting EGFR-dependent compensatory hepatocyte proliferation through integrin α6-mediated ROS accumulation, leading to p53 activation and cell cycle block. Ccn1ΔHep and Ccn1(dm/dm) mice show increased DEN-induced HCC due to diminished p53 activation and elevated compensatory proliferation. Hepatocyte-specific Ccn1 KO mice, knockin mice (α6β1-binding defective), DEN-induced HCC model, ROS measurement, EGFR inhibitor (erlotinib) treatment, p53 activation assay, proliferation assay Oncogene High 26028023
2015 CCN1 is O-fucosylated at Thr242 in its thrombospondin type-1 repeat (TSR1) domain by protein O-fucosyltransferase 2 (POFUT2); loss of O-fucosylation reduces cell-surface localization and secretion of CCN1. Mass spectrometry identification of O-fucosylation site, mutagenesis of Thr242, POFUT2 knockdown, measurement of secreted and cell-surface CCN1 FEBS letters High 26424659
2015 CCN1 binds directly to ADAMTS-4 (aggrecanase-1) through the ADAMTS-4 cysteine-rich domain and inhibits its aggrecanase activity; TGF-β-induced CCN1 expression is sufficient to block ADAMTS-4 aggrecanase activity in chondrocytes, while IL-1α stimulation that downregulates CCN1 allows ADAMTS-4 activity. Nanoscale LC-MS/MS identification, co-immunoprecipitation, solid-phase binding assay, aggrecan digestion assay, siRNA knockdown of CCN1, IL-1α/TGFβ treatment Arthritis & rheumatology High 25709087
2016 CCN1/CYR61 released by activated platelets enables the recruitment of Ly6Clow monocytes to inflamed vascular endothelium; endothelium-bound CCN1 sustains Ly6Clow monocyte patrolling and orchestrates subsequent neutrophil recruitment. Antibody blockade of CCN1 impaired early Ly6Clow monocyte arrival and abolished neutrophil recruitment. Confocal intravital microscopy, CCN1-blocking antibodies, platelet depletion, TLR7/8-mediated inflammation model in mesenteric veins Proceedings of the National Academy of Sciences of the United States of America High 27482114
2018 CCN1/CYR61 regulates sclerostin (Sost) expression in osteocytes/osteoblasts; CCN1 overexpression suppresses Sost, and Sost siRNA rescues Wnt responsiveness in Ccn1 knockout cells. Bone-specific Ccn1 KO mice show decreased bone mass with increased Sost, increased RankL, decreased VegfA, and impaired Wnt signaling. Conditional bone-specific KO mice, microCT bone analysis, in vitro overexpression/siRNA in UMR-106 cells, Axin2 reporter of Wnt signaling, bone vasculature analysis Journal of bone and mineral research High 29351359
2019 Shear stress-induced CCN1 binds integrin α6β1 on endothelial cells to activate NF-κB, inducing atheroprone gene expression and establishing a positive feedback loop where NF-κB further increases CCN1 and α6β1 expression. Ccn1-dm/Apoe-/- knockin mice show marked resistance to ligation-induced atherosclerotic plaque formation. Knockin mouse model (Ccn1-dm/dm; Apoe-/-), carotid artery ligation atherosclerosis model, oscillatory vs. laminar shear stress experiments in ECs, NF-κB reporter assay, integrin-blocking peptide (T1) Circulation High 30917686
2019 CCN1 is a direct target of YAP transcriptional coactivator in endothelial cells; CCN1 overexpression causes nuclear exclusion/inactivation of YAP in a negative feedback loop by providing cells with a soft compliant matrix that creates YAP-repressive cytoskeletal states. EC-specific Ccn1 deletion phenocopies YAP gain-of-function with EC hyperproliferation and vessel enlargement. YAP ChIP on CCN1 promoter, EC-specific Ccn1 KO mice, AAV-mediated CCN1 expression in ischemic retinopathy, YAP nuclear localization assays, pharmacological modulation of cell stiffness Molecular and cellular biology High 31262999
2019 CCN1 activates VEGFR2 and downstream MAPK/PI3K signaling and YAP/TAZ as well as Rho effector mDia1 to enhance endothelial tip cell activity; VEGFR2 interacts with integrin αvβ3 through CCN1, forming a complex that promotes CCN1 expression in a positive feedback loop. Zebrafish ccn1 knockdown, EC-specific Ccn1 transgenic mice, retinal vascular sprouting assay, integrin αvβ3 inhibitor, co-immunoprecipitation of VEGFR2/integrin αvβ3, YAP/TAZ activation assays eLife High 31429823
2020 CCN1 binds bacterial pathogen-associated molecular patterns (peptidoglycans of Gram-positive bacteria and LPS of Gram-negative bacteria), opsonizes MRSA and Pseudomonas aeruginosa for phagocytosis through integrin αvβ3, and directly binds TLR2 and TLR4 to activate MyD88-dependent signaling, cytokine expression, and neutrophil mobilization. Binding assays (peptidoglycan/LPS), phagocytosis assays, ROS production assays, myeloid-specific Ccn1 KO mice, αvβ3-binding knockin mice, in vivo infection models, TLR2/TLR4 direct binding assays, MyD88-dependent signaling analysis Nature communications High 32144270
2022 CCN1 coordinately regulates intestinal stem cell (ISC) proliferation and differentiation through integrins αvβ3/αvβ5: CCN1 induces NF-κB-dependent Jag1 expression to activate Notch signaling for differentiation, and promotes Src-mediated YAP activation and Dkk1 expression to control Wnt signaling for proliferation; CCN1 and YAP amplify each other's activities in a regulatory loop. Ccn1 deletion in Lgr5+ ISCs, knockin mice (αvβ3/αvβ5-binding defective CCN1), crypt organoids, NF-κB reporter, Notch pathway analysis, YAP activation assay, Wnt reporter, intestinal phenotype analysis Nature communications High 35660741
2023 Hepatocyte CCN1 polarizes infiltrating monocytes to a proinflammatory/profibrotic phenotype in NASH through an IRAK4/SYK/NF-κB signaling cascade, inducing PDGFa/PDGFb expression in macrophages; liver-specific CCN1 KO mice show improved glucose tolerance, decreased liver inflammation, and reduced fibrosis on NASH diet. Liver-specific CCN1 KO mice, NASH diet model, in vitro macrophage treatment with CCN1, IRAK4/SYK inhibitors, NF-κB reporter, targeted antibody blockade in vitro and in vivo Science translational medicine High 37756381
2025 Upon ferroptosis induction, CCN1 relocates from extracellular matrix to mitochondrial complexes where it facilitates ETFA-dependent fatty acid β-oxidation, providing additional substrates for mitochondrial ROS production and stimulating ferroptosis through lipid peroxidation. This CCN1-ETFA pathway is distinct from the canonical CPT2-ETFA pathway. Multiomics screening, subcellular fractionation/co-immunoprecipitation of CCN1 with mitochondrial complexes, fatty acid β-oxidation assays, ROS measurement, lipid peroxidation assays, CCN1 KO cells and mouse models, high-fat diet lung cancer models Developmental cell High 40280135
2005 Cyr61/CCN1 protects pulmonary epithelial cells against hyperoxia-induced cell death via Akt activation; siRNA-mediated knockdown of Cyr61 accelerated cell death, while overexpression conferred resistance and induced Akt phosphorylation; siRNA knockdown of Akt abrogated the protective effect. siRNA knockdown of Cyr61 and Akt, Cyr61 overexpression, Akt phosphorylation assay, cell death assays under hyperoxia American journal of respiratory cell and molecular biology Medium 15961723
2008 Caveolin-1 (cav-1) co-localizes and physically interacts with Cyr61 via integrins in bronchial epithelial cells; deletion of cav-1 increases extracellular Cyr61 secretion (by a non-classical, Brefeldin A-inhibitable pathway) and decreases cytosolic Cyr61; the protective effect of cav-1 deletion against hyperoxia requires secreted Cyr61. Co-immunoprecipitation, co-localization by immunofluorescence, cav-1 knockout cells/mice, neutralizing antibody, Brefeldin A treatment, subcellular fractionation FASEB journal Medium 18801924
2014 Full-length CCN1 is secreted in an exosome-shuttled manner; extracellular plasmin cleaves full-length CCN1 to generate a C-terminal fragment (cCCN1) that binds integrin-α7 and promotes MMP-1 production, while full-length CCN1 facilitates IL-8 and VEGF release; the two forms have opposing functions in cigarette smoke-induced lung epithelial injury. Exosome isolation, plasmin cleavage assay, integrin-α7 binding/expression analysis, siRNA knockdown, MMP-1 and VEGF/IL-8 measurement, bronchoalveolar lavage analysis in vivo American journal of physiology. Lung cellular and molecular physiology Medium 24973403
2009 CCN1 supports prostate carcinoma cell adhesion through integrins and heparan sulfate proteoglycans, promotes cell proliferation, and enhances TRAIL-induced apoptosis through integrins αvβ3 and α6β4 and syndecan-4 via a PKCα-dependent mechanism not requiring de novo protein synthesis. Integrin-blocking antibodies, syndecan-4 knockdown, CCN1 siRNA knockdown, TRAIL apoptosis assays, PKCα inhibitors, CCN1 protein rescue Molecular cancer research Medium 19584265
2016 CCN1 promotes chondrocyte maturation and cartilage development downstream of WNT/β-catenin signaling; β-catenin promotes CCN1 expression in chondrocytes, and cartilage-specific CCN1 overexpression in transgenic mice leads to chondrodysplasia and cartilage degeneration. Primary chondrocyte cultures, β-catenin gain/loss-of-function, conditional CCN1 transgenic mice, in vitro chondrocyte maturation assays with CCN1 overexpression/inhibition Journal of bone and mineral research Medium 26363286
2018 CCN1 activates melanogenesis in human epidermal melanocytes through integrin α6β1, and downstream p38 MAPK and ERK1/2 signaling, upregulating MITF, TRP-1, and tyrosinase and promoting melanosome maturation; UVB irradiation stimulates CCN1 secretion from dermal fibroblasts, and CCN1 knockdown in fibroblasts attenuates melanogenesis in co-culture. Recombinant CCN1 treatment, integrin α6β1 blocking antibodies, p38/ERK inhibitors, siRNA knockdown of CCN1 in fibroblasts, melanocyte-fibroblast co-culture, tyrosinase activity assay The Journal of investigative dermatology Medium 29510193
2020 IL-6 stimulates Cyr61 protein synthesis in fibroblast-like synoviocytes via the ERK1/2-EGR3 pathway; Cyr61 promotes FLS migration and invasion in an autocrine manner by upregulating MMP2; knockdown or neutralizing antibody to Cyr61 attenuates IL-6-induced FLS migration. Western blot, siRNA knockdown of EGR3 and JUN, ERK1/2 inhibitor (PD98059), CYR61 neutralizing antibody, wound healing assay, Boyden chamber invasion assay, MMP2 expression analysis Arthritis research & therapy Medium 33228785
2019 CCN1 expression in fibroblasts is required for bleomycin-induced skin fibrosis; fibroblast-specific CCN1 deletion reduces type I collagen stability (via reduced prolyl-4-hydroxylase and PLOD2 expression) and leads to disorganized collagen fibers, while not affecting myofibroblast induction or wound closure kinetics. Fibroblast-specific CCN1 KO mice, bleomycin-induced fibrosis model, electron microscopy of collagen fibers, hydroxyproline assay, qPCR for collagen stability enzymes, wound healing assay Matrix biology plus Medium 33543008
2024 TGF-β-stimulated Smad2/3 and Hippo pathway effectors YAP and TEAD4 form a protein complex on the CYR61 promoter to cooperatively activate CYR61 transcription; CYR61 functions as a tumor suppressor in liver cancer cells, impeding TGF-β- or YAP-induced malignant transformation. ChIP assay on CYR61 promoter, co-immunoprecipitation of Smad2/3-YAP-TEAD4 complex, CYR61 overexpression/depletion, HCC xenograft mouse model, transcriptomic analysis The Journal of biological chemistry Medium 38521502
2017 CCN1 induces CCL20 production in keratinocytes via activation of p38 MAPK and JNK pathways, which enhance AP-1 binding to the CCL20 promoter; in vivo, CCN1 blockade or knockdown reduces CCL20 expression and ameliorates psoriasis-like inflammation in mouse models. Exogenous CCN1 protein treatment of keratinocytes, p38/JNK inhibitors, ChIP assay for AP-1 on CCL20 promoter, siRNA knockdown of CCN1, imiquimod and IL-23 psoriasis mouse models Journal of dermatological science Medium 28602508
2022 3-Mercaptopyruvate sulfurtransferase (3-MST) upregulates CYR61 expression via modulation of S1PR through ATF1 and CREB; endogenously produced CYR61 counteracts apoptosis in part through RhoA activation; inhibition of 3-MST markedly suppresses CYR61 secretion from colon cancer cells. Pharmacological inhibitors of CBS and 3-MST, H2S/polysulfide donors, CYR61 promoter luciferase assay, siRNA knockdown, RhoA activation assay, apoptosis assays Redox biology Medium 36113340
2024 Endogenous CCN1 from fibroblasts is required for collagen fibril organization and scar structural integrity after myocardial infarction; fibroblast-specific CCN1 KO mice show disorganized collagen topography, reduced fibroblast-matrix interactions, and increased cardiac rupture after MI without affecting myofibroblast induction or total collagen mass; CCN1 augments fibroblast focal adhesion formation. Fibroblast-specific CCN1 KO mice, MI (coronary ligation) model, SHG and TEM collagen architecture analysis, focal adhesion assay, in vitro CCN1 siRNA, cardiac function analysis Matrix biology Medium 39098433
2015 CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress by overloading the endoplasmic reticulum, triggering an unfolded protein response (UPR) including IRE1α-JNK, PERK-eIF2a-CHOP activation, and apoptosis via caspase-12, -9, and -3 cleavage; this reduces type I collagen expression. Adenoviral CCN1 overexpression in primary HSC and HSC lines, UPR markers (BIP/GRP78, GRP94, spliced XBP1, CHOP), caspase cleavage assays, TUNEL staining, collagen mRNA/protein measurement Cellular signalling Medium 26515130
2003 In glomerulonephritis, CCN1 expressed by podocytes can inhibit mesangial cell migration; recombinant CCN1 enhanced endothelial cell adhesion while prominently inhibiting mesangial cell adhesion, and induced p27Kip1 and synaptopodin expression in cultured podocytes, suppressing podocyte migration. Recombinant CCN1 treatment, cell adhesion assay, cell migration assay, Western blot for p27Kip1 and synaptopodin, in situ hybridization, immunohistochemistry American journal of physiology. Renal physiology Medium 17699553

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature cell biology 791 20526329
2002 CYR61 (CCN1) is essential for placental development and vascular integrity. Molecular and cellular biology 344 12446788
1990 Expression of cyr61, a growth factor-inducible immediate-early gene. Molecular and cellular biology 292 2355916
2011 CCN1/CYR61: the very model of a modern matricellular protein. Cellular and molecular life sciences : CMLS 284 21805345
1997 Cyr61 and Fisp12 are both ECM-associated signaling molecules: activities, metabolism, and localization during development. Experimental cell research 222 9184077
2006 Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. The FEBS journal 167 16856934
2002 Cyr61 promotes breast tumorigenesis and cancer progression. Oncogene 165 12444554
2010 Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages. Journal of immunology (Baltimore, Md. : 1950) 144 20164416
2015 The matricellular protein CCN1 mediates neutrophil efferocytosis in cutaneous wound healing. Nature communications 141 26077348
2007 Functional properties and intracellular signaling of CCN1/Cyr61. Journal of cellular biochemistry 140 17171641
2007 Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer. PloS one 125 17579708
2003 The angiogenic factor CYR61 in breast cancer: molecular pathology and therapeutic perspectives. Endocrine-related cancer 108 12790776
2011 Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis. Molecular cancer 102 21232118
2005 The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts. The Journal of cell biology 100 16275757
2002 Expression of CYR61, an angiogenic immediate early gene, in arteriosclerosis and its regulation by angiotensin II. Circulation 99 12105167
2000 Temporal expression of the chondrogenic and angiogenic growth factor CYR61 during fracture repair. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 92 10841170
2014 CCN1 secretion and cleavage regulate the lung epithelial cell functions after cigarette smoke. American journal of physiology. Lung cellular and molecular physiology 90 24973403
2014 Matricellular protein CCN1/CYR61: a new player in inflammation and leukocyte trafficking. Seminars in immunopathology 79 24638890
2018 The matricellular protein CCN1 in tissue injury repair. Journal of cell communication and signaling 75 29357009
2002 Expression and regulation of Cyr61 in human breast cancer cell lines. Oncogene 70 11840342
2018 The official unified nomenclature adopted by the HGNC calls for the use of the acronyms, CCN1-6, and discontinuation in the use of CYR61, CTGF, NOV and WISP 1-3 respectively. Journal of cell communication and signaling 69 30393824
2005 Increased expression of Cyr61 (CCN1) identified in peritoneal metastases from human pancreatic cancer. Journal of the American College of Surgeons 69 15737847
2004 Cyr61, a deregulated gene in endometriosis. Molecular human reproduction 68 15044605
2019 Shear-Induced CCN1 Promotes Atheroprone Endothelial Phenotypes and Atherosclerosis. Circulation 67 30917686
2003 Xenopus Cyr61 regulates gastrulation movements and modulates Wnt signalling. Development (Cambridge, England) 67 12702657
2013 Aging increases CCN1 expression leading to muscle senescence. American journal of physiology. Cell physiology 59 24196529
2015 Matricellular proteins of the Cyr61/CTGF/NOV (CCN) family and the nervous system. Frontiers in cellular neuroscience 56 26157362
2012 CCN1: a novel inflammation-regulated biphasic immune cell migration modulator. Cellular and molecular life sciences : CMLS 56 22527715
2015 The matricellular protein CCN1 promotes mucosal healing in murine colitis through IL-6. Mucosal immunology 55 25807183
2022 CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation. Nature communications 54 35660741
2009 Matrix protein CCN1 is critical for prostate carcinoma cell proliferation and TRAIL-induced apoptosis. Molecular cancer research : MCR 54 19584265
2019 CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity. eLife 52 31429823
2016 CCN1/CYR61-mediated meticulous patrolling by Ly6Clow monocytes fuels vascular inflammation. Proceedings of the National Academy of Sciences of the United States of America 52 27482114
2015 CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress-related apoptosis. Cellular signalling 52 26515130
2011 CYR61 downregulation reduces osteosarcoma cell invasion, migration, and metastasis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 52 21312266
2015 Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities. Human genomics 48 26395334
2012 The matricellular protein CCN1/Cyr61 is a critical regulator of Sonic Hedgehog in pancreatic carcinogenesis. The Journal of biological chemistry 47 23027863
2020 CCN1 is an opsonin for bacterial clearance and a direct activator of Toll-like receptor signaling. Nature communications 45 32144270
2010 Cyr61 mediates hepatocyte growth factor-dependent tumor cell growth, migration, and Akt activation. Cancer research 45 20233866
2007 Cyr61/CCN1 is a tumor suppressor in human hepatocellular carcinoma and involved in DNA damage response. The international journal of biochemistry & cell biology 45 17698398
2010 Expression of CTGF and Cyr61 in colorectal cancer. Journal of clinical pathology 44 21081514
2015 The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation. Oncogene 43 26028023
2014 IGF-1 regulates Cyr61 induced breast cancer cell proliferation and invasion. PloS one 42 25062088
2005 Cyr61 protects against hyperoxia-induced cell death via Akt pathway in pulmonary epithelial cells. American journal of respiratory cell and molecular biology 42 15961723
2005 Expression, purification, and functional testing of recombinant CYR61/CCN1. Protein expression and purification 37 15878827
2019 CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma. Molecular cancer therapeutics 36 30787177
2008 Cyr61/CCN1 and CTGF/CCN2 mediate the proangiogenic activity of VHL-mutant renal carcinoma cells. Carcinogenesis 36 18212329
2019 Aberrant activation of CYR61 enhancers in colorectal cancer development. Journal of experimental & clinical cancer research : CR 35 31118064
2014 Pancreatic tumor cell secreted CCN1/Cyr61 promotes endothelial cell migration and aberrant neovascularization. Scientific reports 35 24833309
2015 CCN1/Cyr61-PI3K/AKT signaling promotes retinal neovascularization in oxygen-induced retinopathy. International journal of molecular medicine 34 26459773
2008 Caveolin-1 regulates the secretion and cytoprotection of Cyr61 in hyperoxic cell death. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 18801924
2018 CYR61/CCN1 Regulates Sclerostin Levels and Bone Maintenance. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 33 29351359
2015 CCN1 (Cyr61) Is Overexpressed in Human Osteoarthritic Cartilage and Inhibits ADAMTS-4 (Aggrecanase 1) Activity. Arthritis & rheumatology (Hoboken, N.J.) 33 25709087
2015 CYR61 (CCN1) overexpression induces lung injury in mice. American journal of physiology. Lung cellular and molecular physiology 33 25713320
2021 YAP, CTGF and Cyr61 are overexpressed in tamoxifen-resistant breast cancer and induce transcriptional repression of ERα. Journal of cell science 32 34096606
2014 Induction of the matricellular protein CCN1 through RhoA and MRTF-A contributes to ischemic cardioprotection. Journal of molecular and cellular cardiology 32 25106095
2021 SREBP1 promotes invasive phenotypes by upregulating CYR61/CTGF via the Hippo-YAP pathway. Endocrine-related cancer 31 34821220
2019 Caught between a "Rho" and a hard place: are CCN1/CYR61 and CCN2/CTGF the arbiters of microvascular stiffness? Journal of cell communication and signaling 31 31376071
2007 Endometrial expression of Cyr61: a marker of estrogenic activity in normal and abnormal endometrium. Obstetrics and gynecology 31 17601910
2007 Bacteria induce CTGF and CYR61 expression in epithelial cells in a lysophosphatidic acid receptor-dependent manner. International journal of medical microbiology : IJMM 31 17765657
2022 Regulation of CyR61 expression and release by 3-mercaptopyruvate sulfurtransferase in colon cancer cells. Redox biology 30 36113340
2018 CCN1/Cyr61 Stimulates Melanogenesis through Integrin α6β1, p38 MAPK, and ERK1/2 Signaling Pathways in Human Epidermal Melanocytes. The Journal of investigative dermatology 30 29510193
2017 Biological functions and role of CCN1/Cyr61 in embryogenesis and tumorigenesis in the female reproductive system (Review). Molecular medicine reports 30 29115499
2003 Angiogenic protein Cyr61 is expressed by podocytes in anti-Thy-1 glomerulonephritis. Journal of the American Society of Nephrology : JASN 30 12707386
2017 Lipopolysaccharide-induced CCN1 production enhances interleukin-6 secretion in bronchial epithelial cells. Cell biology and toxicology 29 28638955
2016 CYR61/CCN1 stimulates proliferation and differentiation of osteoblasts in vitro and contributes to bone remodeling in vivo in myeloma bone disease. International journal of oncology 28 28035364
2020 Cyr61 synthesis is induced by interleukin-6 and promotes migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis research & therapy 27 33228785
2016 CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties. Cell adhesion & migration 27 26744771
2019 Long noncoding RNA CPS1-IT1 suppresses melanoma cell metastasis through inhibiting Cyr61 via competitively binding to BRG1. Journal of cellular physiology 26 31111478
2017 Cyr61/CCN1 induces CCL20 production by keratinocyte via activating p38 and JNK/AP-1 pathway in psoriasis. Journal of dermatological science 26 28602508
2015 O-Fucosylation of CCN1 is required for its secretion. FEBS letters 26 26424659
2007 Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney. American journal of physiology. Renal physiology 26 17699553
2004 Induction and function of CYR61 (CCN1) in prostatic stromal and epithelial cells: CYR61 is required for prostatic cell proliferation. The Prostate 26 15389821
2023 Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis. Science translational medicine 24 37756381
2020 CCN1 promotes hepatic steatosis and inflammation in non-alcoholic steatohepatitis. Scientific reports 24 32081971
2013 Matricellular protein Cyr61 bridges lysophosphatidic acid and integrin pathways leading to cell migration. The Journal of biological chemistry 24 24371135
2012 The matrix protein CCN1/CYR61 is required for α(V)β5-mediated cancer cell migration. Cell biochemistry and function 24 22692860
2019 CCN1-Yes-Associated Protein Feedback Loop Regulates Physiological and Pathological Angiogenesis. Molecular and cellular biology 23 31262999
2016 CYR61 (CCN1) is a metastatic biomarker of gastric cardia adenocarcinoma. Oncotarget 23 27105510
2014 CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease. Blood 23 25061178
2019 CCN1 expression by fibroblasts is required for bleomycin-induced skin fibrosis. Matrix biology plus 22 33543008
2016 CCN1 Regulates Chondrocyte Maturation and Cartilage Development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 21 26363286
2014 Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors. Oncogene 21 25065593
1998 Expression of immediate early gene cyr61 during the differentiation of immortalized embryonic hippocampal neuronal cells. Neuroscience letters 21 9832196
2024 Cancer-associated Fibroblast-specific Expression of the Matricellular Protein CCN1 Coordinates Neovascularization and Stroma Deposition in Melanoma Metastasis. Cancer research communications 20 38363129
2024 Upregulation of CYR61 by TGF-β and YAP signaling exerts a counter-suppression of hepatocellular carcinoma. The Journal of biological chemistry 20 38521502
2023 Astragaloside IV improves pulmonary arterial hypertension by increasing the expression of CCN1 and activating the ERK1/2 pathway. Journal of cellular and molecular medicine 20 36762748
2022 Matrix-bound Cyr61/CCN1 is required to retain the properties of the bone marrow mesenchymal stem cell niche but is depleted with aging. Matrix biology : journal of the International Society for Matrix Biology 20 35752272
2014 Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves' disease and ophthalmopathy. Thyroid : official journal of the American Thyroid Association 20 24780075
2024 Matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction. Matrix biology : journal of the International Society for Matrix Biology 19 39098433
2023 MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats. Frontiers in nutrition 19 36687680
2021 Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression. Frontiers in cardiovascular medicine 19 34458333
2014 Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway. Cancer cell international 19 25187756
2022 Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells. Cells 17 35159343
2021 Adriamycin-Induced Podocyte Injury Disrupts the YAP-TEAD1 Axis and Downregulates Cyr61 and CTGF Expression. ACS chemical biology 17 34890187
2020 Dermal Fibroblast CCN1 Expression in Mice Recapitulates Human Skin Dermal Aging. The Journal of investigative dermatology 17 32800875
2017 Recombinant CCN1 prevents hyperoxia-induced lung injury in neonatal rats. Pediatric research 17 28700567
2025 Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation. Developmental cell 16 40280135
2022 Depletion of CCN1/CYR61 reduces triple-negative/basal-like breast cancer aggressiveness. American journal of cancer research 16 35261806
2015 The matricellular protein CCN1 regulates TNF-α induced vascular endothelial cell apoptosis. Cell biology international 16 25820828

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