Details for: GFRA3

Gene ID: 2676

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: GFRA3

Ensembl ID: ENSG00000146013

Description: GDNF family receptor alpha 3

Cell Significance Landscape

Associated with

Significant Cells

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

  • conventional dendritic cell CL0000990
    CSI 33.88
    rCSI 28.28%
    PRS 92.02
  • enteroendocrine cell CL0000164
    CSI 15.61
    rCSI 21.33%
    PRS 95.93
  • neural crest cell CL0011012
    CSI 14.83
    rCSI 11.72%
    PRS 95.37
  • lung neuroendocrine cell CL1000223
    CSI 9.72
    rCSI 14.37%
    PRS 97.18
  • Schwann cell CL0002573
    CSI 7.54
    rCSI 21.43%
    PRS 95.57
  • glial cell CL0000125
    CSI 7.35
    rCSI 28%
    PRS 94.03
  • chondrocyte CL0000138
    CSI 4.39
    rCSI 6.98%
    PRS 95.41
  • melanocyte of skin CL1000458
    CSI 4.3
    rCSI 5.86%
    PRS 79.16
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 3.59
    rCSI 4.35%
    PRS 83.91
  • basal cell of epidermis CL0002187
    CSI 3.29
    rCSI 5.83%
    PRS 78.12
  • P/D1 enteroendocrine cell CL0002268
    CSI 1.5
    rCSI 8.19%
    PRS 96.99
  • suprabasal keratinocyte CL4033013
    CSI 1
    rCSI 1.63%
    PRS 79.68

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):
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    • High
    • Medium
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    • 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 GDNF family receptor alpha 3 ([GFRA3](/details-gene/2676)) is a protein-coding gene located on chromosome 5q31.2. It encodes a glycosylphosphatidylinositol (GPI)-linked cell surface receptor belonging to the GDNF receptor-alpha family. [GFRA3](/details-gene/2676) functions as a co-receptor for the neurotrophic factor artemin, a member of the glial cell line-derived neurotrophic factor (GDNF) family of ligands. Upon binding artemin, [GFRA3](/details-gene/2676) typically forms a complex with the RET proto-oncogene receptor tyrosine kinase, initiating intracellular signaling cascades critical for neuronal survival and development ([Link](https://doi.org/10.1016/s0896-6273(00)80649-2)). While its role is well-established in the development of the peripheral and sympathetic nervous systems, expression data reveals its highest significance in [conventional dendritic cells](/details-cell/CL0000990), with additional high expression in various neuroendocrine and neural crest-derived cell types, suggesting a broader biological role than previously characterized. ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [GFRA3](/details-gene/2676) highlights its importance in both the nervous and immune systems, as well as in specialized neuroendocrine populations. The most significant expression is observed in [conventional dendritic cells](/details-cell/CL0000990) (CSI: 33.88), suggesting a potentially novel and important function in antigen presentation or immune regulation. This is complemented by high significance in cell types classically associated with neurotrophic factor signaling. These include cells of neural crest origin such as [neural crest cells](/details-cell/CL0011012) themselves, peripheral nervous system [Schwann cells](/details-cell/CL0002573), and generalized [glial cells](/details-cell/CL0000125). Furthermore, [GFRA3](/details-gene/2676) is a prominent marker in neuroendocrine lineages, as evidenced by its high significance in [enteroendocrine cells](/details-cell/CL0000164) and [lung neuroendocrine cells](/details-cell/CL1000223). This pattern is consistent with its established function in the development and maintenance of neuronal and neuronal-like cells. Moderate expression is also noted in other cell types including [chondrocytes](/details-cell/CL0000138) and various epidermal cells like [melanocytes](/details-cell/CL1000458) and [basal cells](/details-cell/CL0002187), indicating a pleiotropic role across different tissues. ## Pathways and Molecular Function Functionally, [GFRA3](/details-gene/2676) is annotated as a [glial cell-derived neurotrophic factor receptor](/details-go/GO:0016167) that operates on the [external side of the plasma membrane](/details-go/GO:0009897) as part of a larger [receptor complex](/details-go/GO:0043235). Its primary molecular function is to bind its ligand, artemin, and facilitate signaling through a transmembrane partner, most commonly RET. The biological processes associated with [GFRA3](/details-gene/2676) are dominated by its role in the nervous system. It is integral to [nervous system development](/details-go/GO:0007399), particularly [peripheral nervous system development](/details-go/GO:0007422) and [sympathetic nervous system development](/details-go/GO:0048485). Key processes mediated by this receptor include [axon guidance](/details-go/GO:0007411) and [neuron migration](/details-go/GO:0001764). Consistent with these roles, Reactome pathway analysis places [GFRA3](/details-gene/2676) within the [Ret signaling](/details-reactome/R-HSA-8853659) and [Axon guidance](/details-reactome/R-HSA-422475) pathways. Downstream signaling from the artemin-[GFRA3](/details-gene/2676)-RET complex often proceeds through the [Raf/MAP kinase cascade](/details-reactome/R-HSA-5673001), a crucial pathway for cell survival, proliferation, and differentiation. While these pathways directly explain its role in neuronal cells, its function in [conventional dendritic cells](/details-cell/CL0000990) may involve similar signaling axes to regulate immune cell fate or function. ## Research Directions The strikingly high expression of [GFRA3](/details-gene/2676) in [conventional dendritic cells](/details-cell/CL0000990) represents a significant departure from its canonical role in the nervous system and points toward novel functions in neuro-immune communication. This observation forms the basis for new research avenues. ### Proposed Hypotheses: 1. **[GFRA3](/details-gene/2676) signaling modulates dendritic cell function.** The artemin-[GFRA3](/details-gene/2676) axis may regulate key aspects of dendritic cell biology, such as maturation, cytokine secretion, or the capacity to prime T cell responses. This could represent a mechanism by which signals from surrounding tissues, including neurons, directly influence adaptive immunity. 2. **[GFRA3](/details-gene/2676) is essential for the homeostasis of neuroendocrine populations.** Given its high expression in [enteroendocrine](/details-cell/CL0000164) and [lung neuroendocrine cells](/details-cell/CL1000223), artemin signaling through [GFRA3](/details-gene/2676) may be a critical survival or differentiation factor for these specialized secretory cells, influencing gut motility or respiratory physiology. ### Experimental Approach: To test the hypothesis that [GFRA3](/details-gene/2676) modulates dendritic cell function, a series of *in vitro* experiments could be conducted. Primary human monocytes could be differentiated into dendritic cells and matured in the presence or absence of the [GFRA3](/details-gene/2676) ligand, artemin. The impact on DC function would be assessed by measuring changes in the expression of co-stimulatory molecules (e.g., CD80, CD86) and MHC class II via flow cytometry, quantifying the profile of secreted cytokines (e.g., IL-12p70, IL-10, TNF) by ELISA, and evaluating their ability to stimulate allogeneic T cell proliferation in a mixed lymphocyte reaction. A CRISPR-Cas9 knockout of [GFRA3](/details-gene/2676) in a human cell line capable of DC differentiation (e.g., MUTZ-3) would serve to confirm the specificity of any observed effects. ### Therapeutic Potential: As a cell surface receptor, [GFRA3](/details-gene/2676) is an accessible drug target. Its role in promoting neuronal survival suggests that **agonists** of the [GFRA3](/details-gene/2676) pathway could have therapeutic potential in treating peripheral neuropathies or certain neurodegenerative disorders characterized by the loss of specific neuronal populations. Conversely, given that the artemin-[GFRA3](/details-gene/2676) axis has been implicated in some models of chronic and neuropathic pain, developing **antagonists** may offer a targeted analgesic strategy. If its role in modulating dendritic cell function is confirmed, it could also represent a novel target for immunotherapies, where pathway activation or inhibition could be used to enhance or suppress immune responses in cancer or autoimmunity, respectively.

Genular Protein ID: 1855349509

Symbol: GFRA3_HUMAN

Name: GDNF family receptor alpha-3

UniProtKB Accession Codes:

O60609 B2RA36 B4DMY9 Q6UW20 Q8IUZ2

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CORUM 1 CTD 1 ChiTaRS 1 DIP 1 DNASU 1 DisGeNET 1 EMBL 8 EMDB 1 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 15 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 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRINTS 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9576965

Title: GFRalpha3 is an orphan member of the GDNF/neurturin/persephin receptor family.

PubMed ID: 9576965

DOI: 10.1073/pnas.95.10.5801

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

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: 15340161

Title: Signal peptide prediction based on analysis of experimentally verified cleavage sites.

PubMed ID: 15340161

DOI: 10.1110/ps.04682504

PubMed ID: 9883723

Title: Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex.

PubMed ID: 9883723

DOI: 10.1016/s0896-6273(00)80649-2

PubMed ID: 23333276

Title: SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRalpha1 and RET.

PubMed ID: 23333276

DOI: 10.1016/j.celrep.2012.12.011

PubMed ID: 16765900

Title: Structure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors.

PubMed ID: 16765900

DOI: 10.1016/j.str.2006.05.010

PubMed ID: 31535977

Title: Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands.

PubMed ID: 31535977

DOI: 10.7554/elife.47650

Sequence Information:

  • Length: 400
  • Mass: 44511
  • Checksum: B0BC252FE1F072C7
  • Sequence:
    • MVRPLNPRPL PPVVLMLLLL LPPSPLPLAA GDPLPTESRL MNSCLQARRK CQADPTCSAA 
YHHLDSCTSS ISTPLPSEEP SVPADCLEAA QQLRNSSLIG CMCHRRMKNQ VACLDIYWTV 
HRARSLGNYE LDVSPYEDTV TSKPWKMNLS KLNMLKPDSD LCLKFAMLCT LNDKCDRLRK 
AYGEACSGPH CQRHVCLRQL LTFFEKAAEP HAQGLLLCPC APNDRGCGER RRNTIAPNCA 
LPPVAPNCLE LRRLCFSDPL CRSRLVDFQT HCHPMDILGT CATEQSRCLR AYLGLIGTAM 
TPNFVSNVNT SVALSCTCRG SGNLQEECEM LEGFFSHNPC LTEAIAAKMR FHSQLFSQDW 
PHPTFAVMAH QNENPAVRPQ PWVPSLFSCT LPLILLLSLW