Details for: CCN4

Gene ID: 8840

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CCN4

Ensembl ID: ENSG00000104415

Description: cellular communication network factor 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • fibroblast of lung CL0002553
    CSI 6.85
    rCSI 6.38%
    PRS 96.86
  • hepatic stellate cell CL0000632
    CSI 3.89
    rCSI 14.58%
    PRS 93.83
  • myofibroblast cell CL0000186
    CSI 3.23
    rCSI 4.47%
    PRS 93.96
  • renal interstitial pericyte CL1001318
    CSI 2.87
    rCSI 7.91%
    PRS 94.73
  • mesodermal cell CL0000222
    CSI 2.63
    rCSI 3.16%
    PRS 95.63
  • vascular associated smooth muscle cell CL0000359
    CSI 2.01
    rCSI 6.51%
    PRS 95.11
  • blood vessel smooth muscle cell CL0019018
    CSI 1.58
    rCSI 12.85%
    PRS 95.07
  • pancreatic stellate cell CL0002410
    CSI 1.23
    rCSI 7.17%
    PRS 96.31
  • stromal cell CL0000499
    CSI 1.15
    rCSI 3.23%
    PRS 93.63

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Cellular communication network factor 4 ([CCN4](/details-gene/8840)), also known as WNT1-inducible-signaling pathway protein 1 (WISP1), is a secreted, cysteine-rich matricellular protein belonging to the CCN family. This protein plays a crucial role in cell-cell and cell-matrix interactions, mediating a wide range of biological processes. As its name suggests, [CCN4](/details-gene/8840) is a downstream target of the [Wnt signaling pathway](/details-pathway/GO:0016055) and is implicated in tissue development, wound healing, and inflammation. **Overall**, expression data reveals that [CCN4](/details-gene/8840) is a defining marker of mesenchymal and stromal cell types, with particularly high significance in [fibroblasts of lung](/details-cell/CL0002553), [hepatic stellate cells](/details-cell/CL0000632), and [myofibroblast cells](/details-cell/CL0000186), underscoring its central role in synthesizing and remodeling the extracellular matrix in various tissues. ## Cellular Roles and Expression Landscape The expression profile of [CCN4](/details-gene/8840) highlights its fundamental role in mesenchymal biology and tissue architecture. **Overall**, the gene shows its highest significance in cells responsible for producing connective tissue and mediating structural integrity and repair. It is a top marker for [fibroblast of lung](/details-cell/CL0002553) (CSI: 6.85), a cell type critical for maintaining the lung's structural framework and participating in fibrotic responses. Similarly, its high significance in [hepatic stellate cell](/details-cell/CL0000632) (CSI: 3.89), [myofibroblast cell](/details-cell/CL0000186) (CSI: 3.23), and [pancreatic stellate cell](/details-cell/CL0002410) (CSI: 1.23) points to a key role in organ-specific fibrosis and tissue remodeling upon injury. The gene's prominence extends to cells associated with the vasculature and general connective tissue, including [renal interstitial pericytes](/details-cell/CL1001318), [vascular associated smooth muscle cells](/details-cell/CL0000359), and [stromal cells](/details-cell/CL0000499). This widespread expression across different stromal compartments suggests that [CCN4](/details-gene/8840) functions as a general regulator of mesenchymal cell activity. The expression pattern strongly indicates a primary function within connective tissue homeostasis and pathology, with a specialized role in cells that orchestrate wound healing, fibrosis, and structural support. ## Pathways and Molecular Function Functional annotation confirms the role of [CCN4](/details-gene/8840) as a secreted signaling protein that modulates the cellular microenvironment. Its localization to the [extracellular space](/details-pathway/GO:0005615) and [extracellular matrix](/details-pathway/GO:0031012) is central to its function. Molecularly, it exerts its effects through [integrin binding](/details-pathway/GO:0005178) and [heparin binding](/details-pathway/GO:0008201), allowing it to interact with both cell surfaces and other matrix components to mediate [cell adhesion](/details-pathway/GO:0007155) and [signal transduction](/details-pathway/GO:0007165). Consistent with its expression in fibroblasts and stellate cells, [CCN4](/details-gene/8840) is heavily involved in processes like [positive regulation of wound healing](/details-pathway/GO:0090303), [bone development](/details-pathway/GO:0060348), and [positive regulation of osteoblast differentiation](/details-pathway/GO:0045669). Its role as a key downstream effector of the [Wnt signaling pathway](/details-pathway/GO:0016055) is well-established and has been shown to be oncogenic ([Link](https://pubmed.ncbi.nlm.nih.gov/10716946/)). Furthermore, its involvement in the [positive regulation of inflammatory response](/details-pathway/GO:0050729) and [regulation of cytokine production](/details-pathway/GO:0001817) suggests it acts as a crucial communication link between tissue stroma and the immune system during injury and disease. Studies have also implicated [CCN4](/details-gene/8840) in attenuating p53-mediated apoptosis, providing a potential mechanism for its pro-survival functions in cancer ([Link](https://doi.org/10.1101/gad.942902)). ## Research Directions The established roles of [CCN4](/details-gene/8840) in Wnt signaling, cell survival, and matrix remodeling, combined with its high expression in stromal cells that become activated in disease, position it as a critical factor in both fibrosis and cancer progression. Research has indicated its aberrant expression in human colon and gastric carcinomas ([Link](https://doi.org/10.1073/pnas.95.25.14717), [Link](https://doi.org/10.1038/sj.onc.1204723)). Based on the available data, several testable hypotheses can be proposed: 1. **Hypothesis 1:** In chronic organ injury (e.g., liver or pulmonary fibrosis), local insults trigger sustained upregulation of [CCN4](/details-gene/8840) in resident fibroblasts and stellate cells, which in turn drives their differentiation into pro-fibrotic [myofibroblasts](/details-cell/CL0000186), leading to excessive extracellular matrix deposition. 2. **Hypothesis 2:** In the tumor microenvironment, [CCN4](/details-gene/8840) secreted by cancer-associated fibroblasts (CAFs) acts in a paracrine manner on adjacent tumor cells to promote epithelial-to-mesenchymal transition (EMT), enhance cell migration, and confer resistance to apoptosis by activating the Akt and Wnt signaling pathways. A key experiment to test the second hypothesis would be to utilize a co-culture system. CRISPR-Cas9 could be used to knock out [CCN4](/details-gene/8840) in primary human CAFs isolated from colorectal tumors. These [CCN4](/details-gene/8840)-knockout CAFs and their wild-type counterparts would then be co-cultured with colorectal cancer cell lines. The impact on cancer cell phenotype could be assessed by measuring changes in cell proliferation (e.g., via IncuCyte analysis), migration and invasion (e.g., via transwell assays), and the expression of EMT markers (e.g., E-cadherin, N-cadherin, Vimentin) using qRT-PCR and western blotting. **Therapeutic Potential:** Given that [CCN4](/details-gene/8840) is a secreted, pro-fibrotic, and pro-tumorigenic protein, it represents a highly promising therapeutic target. Its extracellular location makes it readily accessible to biologic drugs. A strategy of **inhibition** using a neutralizing monoclonal antibody that blocks the binding of [CCN4](/details-gene/8840) to cell surface receptors like integrins could be effective. Such a therapy could potentially disrupt the pathological feedback loops that drive fibrosis and tumor progression, making it a candidate for treating a range of fibrotic diseases and cancers where stromal activation is a key feature.

Genular Protein ID: 2545949614

Symbol: CCN4_HUMAN

Name: WNT1-inducible-signaling pathway protein 1

UniProtKB Accession Codes:

O95388 A8KAG6 E7EMM5 Q5JBS6 Q5JBS7 Q5JBS8 Q9HCS3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 4 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 11 Ensembl 4 ExpressionAtlas 1 GO 23 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 11 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PIRSF 1 PRO 1 PROSITE 7 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 5 RNAct 1 RefSeq 4 SIGNOR 1 SMART 4 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9843955

Title: WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors.

PubMed ID: 9843955

DOI: 10.1073/pnas.95.25.14717

PubMed ID: 11571650

Title: A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma.

PubMed ID: 11571650

DOI: 10.1038/sj.onc.1204723

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16421571

Title: DNA sequence and analysis of human chromosome 8.

PubMed ID: 16421571

DOI: 10.1038/nature04406

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 10716946

Title: WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene.

PubMed ID: 10716946

PubMed ID: 11782444

Title: WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase.

PubMed ID: 11782444

DOI: 10.1101/gad.942902

PubMed ID: 11598131

Title: WISP-1 binds to decorin and biglycan.

PubMed ID: 11598131

DOI: 10.1074/jbc.m108339200

Sequence Information:

  • Length: 367
  • Mass: 40331
  • Checksum: 9F29CA94D69C0502
  • Sequence:
    • MRWFLPWTLA AVTAAAASTV LATALSPAPT TMDFTPAPLE DTSSRPQFCK WPCECPPSPP 
RCPLGVSLIT DGCECCKMCA QQLGDNCTEA AICDPHRGLY CDYSGDRPRY AIGVCAQVVG 
VGCVLDGVRY NNGQSFQPNC KYNCTCIDGA VGCTPLCLRV RPPRLWCPHP RRVSIPGHCC 
EQWVCEDDAK RPRKTAPRDT GAFDAVGEVE AWHRNCIAYT SPWSPCSTSC GLGVSTRISN 
VNAQCWPEQE SRLCNLRPCD VDIHTLIKAG KKCLAVYQPE ASMNFTLAGC ISTRSYQPKY 
CGVCMDNRCC IPYKSKTIDV SFQCPDGLGF SRQVLWINAC FCNLSCRNPN DIFADLESYP 
DFSEIAN