Details for: EREG

Gene ID: 2069

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: EREG

Ensembl ID: ENSG00000124882

Description: epiregulin

Cell Significance Landscape

Associated with

Significant Cells

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

  • intermediate monocyte CL0002393
    CSI 16.51
    rCSI 24.9%
    PRS 82.52
  • hematopoietic stem cell CL0000037
    CSI 16.3
    rCSI 10.83%
    PRS 80.02
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 11.54
    rCSI 13.94%
    PRS 85.02
  • myeloid dendritic cell CL0000782
    CSI 10.41
    rCSI 15.08%
    PRS 89.74
  • colon macrophage CL0009038
    CSI 9.32
    rCSI 43.06%
    PRS 89.85
  • monocyte CL0000576
    CSI 8.59
    rCSI 15.52%
    PRS 83.31
  • CD14-positive, CD16-negative classical monocyte CL0002057
    CSI 7.61
    rCSI 46.01%
    PRS 88.89
  • enterocyte CL0000584
    CSI 7.59
    rCSI 12.23%
    PRS 76.78
  • conventional dendritic cell CL0000990
    CSI 7.27
    rCSI 6.07%
    PRS 79.1
  • VIP GABAergic cortical interneuron CL4023016
    CSI 6.48
    rCSI 7.73%
    PRS 58.85
  • luminal epithelial cell of mammary gland CL0002326
    CSI 5.9
    rCSI 10.72%
    PRS 88.02
  • goblet cell CL0000160
    CSI 5.7
    rCSI 5.38%
    PRS 76.13
  • elicited macrophage CL0000861
    CSI 5.49
    rCSI 5.04%
    PRS 85.23
  • CD14-positive monocyte CL0001054
    CSI 5.23
    rCSI 6.51%
    PRS 86.36
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 4.71
    rCSI 6.17%
    PRS 87.98
  • intestine goblet cell CL0019031
    CSI 4.5
    rCSI 4%
    PRS 75.03
  • common myeloid progenitor CL0000049
    CSI 4
    rCSI 3.23%
    PRS 79.55
  • mononuclear phagocyte CL0000113
    CSI 3.66
    rCSI 8.06%
    PRS 81.06
  • squamous epithelial cell CL0000076
    CSI 3.47
    rCSI 8.22%
    PRS 78.19
  • inflammatory macrophage CL0000863
    CSI 3.45
    rCSI 5.89%
    PRS 92.62
  • alternatively activated macrophage CL0000890
    CSI 2.99
    rCSI 3.76%
    PRS 86.68
  • group 3 innate lymphoid cell CL0001071
    CSI 2.99
    rCSI 2.25%
    PRS 83.02
  • alveolar macrophage CL0000583
    CSI 2.89
    rCSI 4.77%
    PRS 81.51
  • hematopoietic multipotent progenitor cell CL0000837
    CSI 2.54
    rCSI 6.12%
    PRS 90.53
  • club cell CL0000158
    CSI 2.43
    rCSI 3.55%
    PRS 71.75
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 2.4
    rCSI 1.85%
    PRS 79.77
  • megakaryocyte CL0000556
    CSI 2.35
    rCSI 10.21%
    PRS 83.51
  • colon epithelial cell CL0011108
    CSI 2.21
    rCSI 2.31%
    PRS 74.44
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.18
    rCSI 1.97%
    PRS 75.21
  • BEST4+ enteroycte CL4030026
    CSI 1.9
    rCSI 2.37%
    PRS 78.56
  • lung macrophage CL1001603
    CSI 1.79
    rCSI 4%
    PRS 84.51
  • dendritic cell, human CL0001056
    CSI 1.7
    rCSI 2.62%
    PRS 85.67
  • colon goblet cell CL0009039
    CSI 1.29
    rCSI 3.08%
    PRS 83.29
  • intestinal epithelial cell CL0002563
    CSI 1.2
    rCSI 1.25%
    PRS 74.9
  • promonocyte CL0000559
    CSI 1.17
    rCSI 2%
    PRS 83.86
  • metallothionein-positive alveolar macrophage CL4033042
    CSI 1.01
    rCSI 11%
    PRS 88.34
  • paneth cell of epithelium of small intestine CL1000343
    CSI 0.81
    rCSI 2.26%
    PRS 85.12
  • paneth cell of colon CL0009009
    CSI 0.38
    rCSI 3.71%
    PRS 87.11

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.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • 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 Epiregulin ([EREG](/details-gene/2069)) is a protein-coding gene located on chromosome 4q13.3 that encodes a member of the epidermal growth factor (EGF) family of signaling ligands. As a growth factor, it functions by binding to and activating the epidermal growth factor receptor (EGFR) and ERBB4, which triggers intracellular signaling cascades involved in cell proliferation, differentiation, and migration ([Link](https://doi.org/10.1038/sj.onc.1201458)). **Overall**, expression data reveals a significant role for [EREG](/details-gene/2069) in the hematopoietic system, with particularly high significance in myeloid lineage cells such as [intermediate monocytes](/details-cell/CL0002393), [hematopoietic stem cells](/details-cell/CL0000037), and various [dendritic cell](/details-cell/CL0000782) populations. Its expression is also notable in specific epithelial contexts, including [enterocytes](/details-cell/CL0000584), suggesting a dual function in both immune regulation and tissue homeostasis. Its association with EGFR/ERBB signaling pathways implicates it in numerous physiological processes, including wound healing and angiogenesis, as well as pathological conditions like cancer ([Link](https://doi.org/10.1016/j.semcdb.2014.03.005)). ## Cellular Roles and Expression Landscape The expression profile of [EREG](/details-gene/2069) highlights its prominent role within the innate immune system, specifically among myeloid cells. **Overall**, the gene shows the highest significance in [intermediate monocytes](/details-cell/CL0002393) (CSI: 16.51), followed closely by [hematopoietic stem cells](/details-cell/CL0000037) (CSI: 16.30). This pattern of high expression extends across the monocyte-macrophage-dendritic cell axis, including [CD1c-positive myeloid dendritic cells](/details-cell/CL0002399), [colon macrophages](/details-cell/CL0009038), and various subsets of [monocytes](/details-cell/CL0000576). This suggests that [EREG](/details-gene/2069) is a key secreted factor involved in the function of these professional antigen-presenting and phagocytic cells, potentially mediating communication with other immune and non-immune cells during inflammation and tissue repair. Beyond its role in immunity, [EREG](/details-gene/2069) is also significantly expressed in certain non-hematopoietic cell types. Its notable significance in intestinal [enterocytes](/details-cell/CL0000584) and [luminal epithelial cells of the mammary gland](/details-cell/CL0002326) points to a function in epithelial tissue maintenance, barrier function, and regeneration. The expression in [hematopoietic stem cells](/details-cell/CL0000037) further suggests a potential role in regulating hematopoiesis or maintaining the stem cell niche. The expression landscape is thus characterized by a specialized distribution in myeloid and select epithelial lineages, consistent with its function as a potent mitogen involved in inflammation, wound healing, and tissue remodeling. ## Pathways and Molecular Function The functional annotations for [EREG](/details-gene/2069) confirm its identity as a versatile signaling ligand. Its primary molecular function is categorized as [growth factor activity](/details-gene/GO:0008083) and [epidermal growth factor receptor binding](/details-gene/GO:0005154). It is a key activator of the [Epidermal growth factor receptor signaling pathway](/details-gene/GO:0007173), as well as signaling through other ERBB family members such as ERBB2 and ERBB4. Reactome pathway analysis further details its deep integration into canonical growth factor signaling networks, including [Signaling by EGFR](/details-gene/R-HSA-177929), [Signaling by ERBB2](/details-gene/R-HSA-1227986), and the downstream [Raf/map kinase cascade](/details-gene/R-HSA-5673001) and [PIP3 activates AKT signaling](/details-gene/R-HSA-1257604) pathways. These signaling activities translate into a broad range of biological processes. [EREG](/details-gene/2069) is implicated in the positive regulation of cell proliferation ([GO:0008284](https://www.ebi.ac.uk/QuickGO/term/GO:0008284)), [angiogenesis](/details-gene/GO:0001525), and [wound healing](/details-gene/GO:0042060). Its involvement in the [positive regulation of innate immune response](/details-gene/GO:0045089) and [cytokine production](/details-gene/GO:0001819) is consistent with its high expression in myeloid cells, positioning it as a mediator that links tissue damage to inflammatory and reparative responses. Furthermore, its role in numerous cancer-related pathways, such as [Signaling by EGFR in cancer](/details-gene/R-HSA-1643713) and [PI3K/AKT signaling in cancer](/details-gene/R-HSA-2219528), underscores its clinical relevance in oncology. ## Research Directions The specific expression pattern of [EREG](/details-gene/2069) in both immune and epithelial cells, combined with its function as a potent EGFR ligand, gives rise to several testable hypotheses. 1. **Hypothesis 1:** [EREG](/details-gene/2069) secreted by monocytes and macrophages at sites of intestinal injury acts as a critical paracrine signal to promote the proliferation and migration of adjacent [enterocytes](/details-cell/CL0000584), thereby accelerating mucosal healing and barrier restoration. 2. **Hypothesis 2:** Within the bone marrow, [EREG](/details-gene/2069) produced by [hematopoietic stem cells](/details-cell/CL0000037) or niche-resident myeloid cells functions as an autocrine/paracrine factor that biases hematopoietic progenitor differentiation towards the myeloid lineage, particularly during periods of hematopoietic stress or infection. **Experimental Approach for Hypothesis 1:** To investigate the role of monocyte-derived [EREG](/details-gene/2069) in epithelial repair, a co-culture system could be established. Primary human [monocytes](/details-cell/CL0000576) would be isolated and activated with an inflammatory stimulus (e.g., LPS). The resulting conditioned medium, rich in secreted factors, would be collected and applied to an intestinal epithelial cell line (e.g., Caco-2) grown in a transwell plate that has been mechanically 'wounded'. The rate of wound closure (migration) and cell proliferation (e.g., via EdU incorporation) would be measured. A parallel experiment would be conducted where the conditioned medium is pre-incubated with a specific EREG-neutralizing antibody. A significant reduction in epithelial repair in the antibody-treated group would confirm that [EREG](/details-gene/2069) is a key functional component of the monocyte secretome driving this process. **Therapeutic Potential:** As a ligand that activates the frequently dysregulated EGFR/ERBB signaling pathways in cancer, [EREG](/details-gene/2069) represents a promising therapeutic target. Overexpression of [EREG](/details-gene/2069) can create a ligand-dependent autocrine or paracrine loop that drives tumor growth. Therefore, therapeutic strategies based on **inhibition** would be most relevant. This could involve the development of monoclonal antibodies that neutralize circulating [EREG](/details-gene/2069) or small molecules that prevent its binding to EGFR/ERBB4. Such an approach could serve as an alternative or a combinatorial therapy alongside existing EGFR inhibitors, potentially overcoming certain resistance mechanisms or reducing off-target effects associated with direct receptor blockade.

Genular Protein ID: 890993416

Symbol: EREG_HUMAN

Name: Proepiregulin

UniProtKB Accession Codes:

O14944 B2RC66 Q6FH69

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEMBL 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 6 EMDB 1 Ensembl 1 EvolutionaryTrace 1 GO 43 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 8 PDBsum 8 PRINTS 1 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 28 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9337852

Title: Distribution of mRNA for human epiregulin, a differentially expressed member of the epidermal growth factor family.

PubMed ID: 9337852

DOI: 10.1042/bj3260069

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

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: 9419975

Title: Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4.

PubMed ID: 9419975

DOI: 10.1038/sj.onc.1201458

PubMed ID: 14572630

Title: Solution structure of epiregulin and the effect of its C-terminal domain for receptor binding affinity.

PubMed ID: 14572630

DOI: 10.1016/s0014-5793(03)01005-6

PubMed ID: 24631357

Title: Epiregulin: roles in normal physiology and cancer.

PubMed ID: 24631357

DOI: 10.1016/j.semcdb.2014.03.005

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

Sequence Information:

  • Length: 169
  • Mass: 19044
  • Checksum: 17F3926ADFB2BDEE
  • Sequence:
    • MTAGRRMEML CAGRVPALLL CLGFHLLQAV LSTTVIPSCI PGESSDNCTA LVQTEDNPRV 
AQVSITKCSS DMNGYCLHGQ CIYLVDMSQN YCRCEVGYTG VRCEHFFLTV HQPLSKEYVA 
LTVILIILFL ITVVGSTYYF CRWYRNRKSK EPKKEYERVT SGDPELPQV