CCN4 Gene

Name cellular communication network factor 4
Description This gene encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. WNT1 is a member of a family of cysteine-rich, glycosylated signaling proteins that mediate diverse developmental processes. The CTGF family members are characterized by four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like domain. This gene may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. It is expressed at a high level in fibroblast cells, and overexpressed in colon tumors. The encoded protein binds to decorin and biglycan, two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue, and possibly prevents the inhibitory activity of decorin and biglycan in tumor cell proliferation. It also attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. It is 83% identical to the mouse protein at the amino acid level. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2011]
Summary
{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CCN4, also known as Wnt1‐inducible signaling protein 1 (WISP1), is a secreted matricellular protein of the CCN family that regulates many key cellular processes including proliferation, differentiation, survival, and extracellular matrix (ECM) production. In pulmonary fibrosis, for example, CCN4 is up‐regulated in alveolar epithelial type II cells and lung fibroblasts, where it promotes epithelial–mesenchymal transition (EMT), cell hyperplasia, and ECM deposition; neutralizing CCN4 in animal models reverses fibrotic gene expression and improves lung function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In joint tissues, elevated CCN4 expression is associated with osteoarthritis; CCN4 stimulates both chondrocytes and macrophages to express matrix metalloproteinases and aggrecanases that lead to cartilage degradation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n CCN4 expression is also implicated in cancer biology. In breast carcinomas, altered CCN4 levels correlate with tumor stage, size, and HER-2/neu status"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", while in lung cancers, increased CCN4 expression is linked to tumor histology and metastatic parameters; mechanistic studies further show that CCN4 can inhibit cell invasion by modulating integrin-mediated Rac activation and down-regulating metalloproteinases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the skeletal system, CCN4 promotes osteogenesis by enhancing bone morphogenetic protein-2 (BMP-2) activity; it stimulates Smad1/5/8 phosphorylation via integrin (α5β1) binding, thereby accelerating osteoprogenitor differentiation and new bone formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cardiac tissue, CCN4 has cytoprotective and remodeling roles. It attenuates doxorubicin-induced cardiomyocyte apoptosis by suppressing pro-apoptotic signaling and by restoring anti-apoptotic and survival pathways"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and it also modulates post-infarct remodeling by promoting cardiac fibroblast proliferation and collagen production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, CCN4 is involved in tissue repair and metabolic regulation. In intestinal mucosal injury, macrophage-derived IL-10 triggers CREB activation, which in turn induces CCN4 production; this CCN4 then activates epithelial pro-proliferative pathways to accelerate wound closure."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Additionally, CCN4 is expressed during adipocyte differentiation and acts as an adipokine; its secretion can provoke a pro-inflammatory response from macrophages and link obesity to low-grade inflammation and insulin resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, CCN4 can further influence Wnt/β-catenin signaling and related pathways; studies demonstrate that modulation of upstream Wnt signals (such as via Wnt5b and mechanical strain) can affect CCN4 expression and thereby impact cell fate decisions in multiple tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies reveal that CCN4 functions as a critical integrator of extracellular cues in diverse physiological and pathological contexts—ranging from fibrosis, joint degeneration, and myocardial remodeling to cancer progression and metabolic regulation—highlighting its potential as a therapeutic target in multiple diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Melanie Königshoff, Monika Kramer, Nisha Balsara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI33950"}], "href": "https://doi.org/10.1172/JCI33950"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19287097"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19287097"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Arjen B Blom, Sarah M Brockbank, Peter L van Lent, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Rheum (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/art.24247"}], "href": "https://doi.org/10.1002/art.24247"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19180479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19180479"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "D Xie, K Nakachi, H Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2001)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11751417"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11751417"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ping-Ping Chen, Wen-Jie Li, Yan Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0000534"}], "href": "https://doi.org/10.1371/journal.pone.0000534"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17579708"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17579708"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lilian L Soon, Ting-An Yie, Anita Shvarts, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M210945200"}], "href": "https://doi.org/10.1074/jbc.M210945200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12529380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12529380"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mitsuaki Ono, Colette A Inkson, Tina M Kilts, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.205"}], "href": "https://doi.org/10.1002/jbmr.205"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20684029"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20684029"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Balachandar Venkatesan, Sumanth D Prabhu, Kaliyamurthi Venkatachalam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2010.01.005"}], "href": "https://doi.org/10.1016/j.cellsig.2010.01.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20074638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20074638"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kaliyamurthi Venkatachalam, Balachandar Venkatesan, Anthony J Valente, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WISP1, a pro-mitogenic, pro-survival factor, mediates tumor necrosis factor-alpha (TNF-alpha)-stimulated cardiac fibroblast proliferation but inhibits TNF-alpha-induced cardiomyocyte death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M809757200"}], "href": "https://doi.org/10.1074/jbc.M809757200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19339243"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19339243"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "J T Colston, S D de la Rosa, M Koehler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.00428.2007"}], "href": "https://doi.org/10.1152/ajpheart.00428.2007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17616748"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17616748"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Miguel Quiros, Hikaru Nishio, Philipp A Neumann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI90229"}], "href": "https://doi.org/10.1172/JCI90229"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28783045"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28783045"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Veronica Murahovschi, Olga Pivovarova, Iryna Ilkavets, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WISP1 is a novel adipokine linked to inflammation in obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db14-0444"}], "href": "https://doi.org/10.2337/db14-0444"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25281430"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25281430"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Akio Kanazawa, Shuichi Tsukada, Masumi Kamiyama, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Beta-catenin levels influence rapid mechanical responses in osteoblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M801907200"}], "href": "https://doi.org/10.1074/jbc.M801907200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18723514"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18723514"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Weiwei Tao, Chengwei Chu, Wenchao Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-020-16827-z"}], "href": "https://doi.org/10.1038/s41467-020-16827-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32541784"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32541784"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Barbara Berschneider, Melanie Königshoff "}, {"type": "b", "children": [{"type": "t", "text": "WNT1 inducible signaling pathway protein 1 (WISP1): a novel mediator linking development and disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biochem Cell Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biocel.2010.11.013"}], "href": "https://doi.org/10.1016/j.biocel.2010.11.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21109017"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21109017"}]}]}]}
NCBI Gene ID 8840
API
Download Associations
Predicted Functions View CCN4's ARCHS4 Predicted Functions.
Co-expressed Genes View CCN4's ARCHS4 Predicted Functions.
Expression in Tissues and Cell Lines View CCN4's ARCHS4 Predicted Functions.

Functional Associations

CCN4 has 2,210 functional associations with biological entities spanning 6 categories (chemical, functional term, phrase or reference, disease, phenotype or trait, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 32 datasets.

Click the + buttons to view associations for CCN4 from the datasets below.

If available, associations are ranked by standardized value

Dataset Summary
Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles tissue samples with high or low expression of CCN4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
Carcinogenome Chemical Perturbation Carcinogenicity Signatures small molecule perturbations changing expression of CCN4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
CellMarker Gene-Cell Type Associations cell types associated with CCN4 gene from the CellMarker Gene-Cell Type Associations dataset.
CM4AI KOLF21J CRISPRi Gene Perturbation Atlas gene perturbations changing expression of CCN4 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
COMPARTMENTS Curated Protein Localization Evidence Scores 2025 cellular components containing CCN4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 cellular components containing CCN4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 cellular components co-occuring with CCN4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
DISEASES Curated Gene-Disease Association Evidence Scores 2025 diseases involving CCN4 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
DISEASES Experimental Gene-Disease Association Evidence Scores 2025 diseases associated with CCN4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
DISEASES Text-mining Gene-Disease Association Evidence Scores 2025 diseases co-occuring with CCN4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
GlyGen Glycosylated Proteins ligands (chemical) binding CCN4 protein from the GlyGen Glycosylated Proteins dataset.
GO Biological Process Annotations 2025 biological processes involving CCN4 gene from the curated GO Biological Process Annotations2025 dataset.
GTEx eQTL 2025 SNPs regulating expression of CCN4 gene from the GTEx eQTL 2025 dataset.
GTEx Tissue Gene Expression Profiles 2023 tissues with high or low expression of CCN4 gene relative to other tissues from the GTEx Tissue Gene Expression Profiles 2023 dataset.
GTEx Tissue-Specific Aging Signatures tissue samples with high or low expression of CCN4 gene relative to other tissue samples from the GTEx Tissue-Specific Aging Signatures dataset.
GWAS Catalog SNP-Phenotype Associations 2025 phenotypes associated with CCN4 gene in GWAS datasets from the GWAS Catalog SNP-Phenotype Associations 2025 dataset.
HuBMAP ASCT+B Annotations cell types associated with CCN4 gene from the HuBMAP ASCT+B dataset.
HuBMAP ASCT+B Augmented with RNA-seq Coexpression cell types associated with CCN4 gene from the HuBMAP ASCT+B Augmented with RNA-seq Coexpression dataset.
HuBMAP Azimuth Cell Type Annotations cell types associated with CCN4 gene from the HuBMAP Azimuth Cell Type Annotations dataset.
JASPAR Predicted Human Transcription Factor Targets 2025 transcription factors regulating expression of CCN4 gene predicted using known transcription factor binding site motifs from the JASPAR Predicted Human Transcription Factor Targets dataset.
JASPAR Predicted Mouse Transcription Factor Targets 2025 transcription factors regulating expression of CCN4 gene predicted using known transcription factor binding site motifs from the JASPAR Predicted Mouse Transcription Factor Targets 2025 dataset.
KEGG Pathways 2026 pathways involving CCN4 protein from the KEGG Pathways 2026 dataset.
LINCS L1000 CMAP Chemical Perturbation Consensus Signatures small molecule perturbations changing expression of CCN4 gene from the LINCS L1000 CMAP Chemical Perturbations Consensus Signatures dataset.
NIBR DRUG-seq U2OS MoA Box Gene Expression Profiles drug perturbations changing expression of CCN4 gene from the NIBR DRUG-seq U2OS MoA Box dataset.
PFOCR Pathway Figure Associations 2024 pathways involving CCN4 protein from the Wikipathways PFOCR 2024 dataset.
Rummagene Transcription Factor Associations 2026 transcription factors regulating expression of CCN4 gene from the Rummagene Transcription Factor Associations 2026 dataset.
RummaGEO Drug Perturbation Signatures drug perturbations changing expression of CCN4 gene from the RummaGEO Drug Perturbation Signatures dataset.
RummaGEO Gene Perturbation Signatures gene perturbations changing expression of CCN4 gene from the RummaGEO Gene Perturbation Signatures dataset.
Tahoe Therapeutics Tahoe 100M Perturbation Atlas drug perturbations changing expression of CCN4 gene from the Tahoe Therapeutics Tahoe 100M Perturbation Atlas dataset.
TISSUES Curated Tissue Protein Expression Evidence Scores 2025 tissues with high expression of CCN4 protein from the TISSUES Curated Tissue Protein Expression Evidence Scores 2025 dataset.
TISSUES Experimental Tissue Protein Expression Evidence Scores 2025 tissues with high expression of CCN4 protein in proteomics datasets from the TISSUES Experimental Tissue Protein Expression Evidence Scores 2025 dataset.
TISSUES Text-mining Tissue Protein Expression Evidence Scores 2025 tissues co-occuring with CCN4 protein in abstracts of biomedical publications from the TISSUES Text-mining Tissue Protein Expression Evidence Scores 2025 dataset.