Details for: FADD

Gene ID: 8772

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: FADD

Ensembl ID: ENSG00000168040

Description: Fas associated via death domain

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • melanocyte of skin CL1000458
    CSI 7.5
    rCSI 10.22%
    PRS 64.85
  • basal cell of epidermis CL0002187
    CSI 4.58
    rCSI 8.12%
    PRS 65.16
  • neural crest cell CL0011012
    CSI 3.46
    rCSI 2.73%
    PRS 86.17
  • duct epithelial cell CL0000068
    CSI 2.82
    rCSI 4.12%
    PRS 94.9
  • peripheral nervous system neuron CL2000032
    CSI 2.7
    rCSI 3.68%
    PRS 86.32
  • suprabasal keratinocyte CL4033013
    CSI 2.66
    rCSI 4.34%
    PRS 65.24
  • intestinal epithelial cell CL0002563
    CSI 2.56
    rCSI 2.68%
    PRS 90.07
  • mesodermal cell CL0000222
    CSI 2.44
    rCSI 2.93%
    PRS 91.19
  • stem cell CL0000034
    CSI 2.3
    rCSI 2.22%
    PRS 88.58
  • chondrocyte CL0000138
    CSI 2.28
    rCSI 3.63%
    PRS 88.22
  • colon epithelial cell CL0011108
    CSI 2.28
    rCSI 2.39%
    PRS 90.09
  • transit amplifying cell of colon CL0009011
    CSI 2.26
    rCSI 2.65%
    PRS 92.06
  • cytotoxic T cell CL0000910
    CSI 2.2
    rCSI 12.63%
    PRS 90.76
  • placental villous trophoblast CL2000060
    CSI 2.15
    rCSI 3.32%
    PRS 90.44
  • common myeloid progenitor CL0000049
    CSI 2.08
    rCSI 1.68%
    PRS 93.17
  • innate lymphoid cell CL0001065
    CSI 2.07
    rCSI 4.26%
    PRS 86.51
  • club cell CL0000158
    CSI 1.85
    rCSI 2.71%
    PRS 88.39
  • mesenchymal cell CL0008019
    CSI 1.48
    rCSI 3.76%
    PRS 87.81
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 1.35
    rCSI 1.64%
    PRS 73.99
  • helper T cell CL0000912
    CSI 1.3
    rCSI 1.84%
    PRS 87.98
  • platelet CL0000233
    CSI 0.83
    rCSI 3.44%
    PRS 88.35

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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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 [FADD](/details-gene/8772) (Fas Associated Via Death Domain) is a crucial adaptor protein that plays a central role in regulating programmed cell death and innate immunity. It contains a death domain (DD) and a death effector domain (DED), which enable it to act as a bridge between cell surface death receptors, such as FAS and TNFR1, and initiator caspases like CASP8 [Link](https://doi.org/10.1016/0092-8674(95)90071-3). Upon receptor activation, [FADD](/details-gene/8772) is recruited to form the Death-Inducing Signaling Complex (DISC), which leads to the activation of the caspase cascade and subsequent execution of apoptosis [Link](https://doi.org/10.1093/emboj/16.10.2794). **Overall**, expression data highlights its high significance in ectoderm-derived tissues, with top markers including `[melanocyte of skin](/details-cell/CL1000458)` and `[basal cell of epidermis](/details-cell/CL0002187)`, suggesting a fundamental role in tissue homeostasis and stress response in barrier organs. Its involvement is clinically associated with OMIM entry [602457](https://omim.org/entry/602457). ## Cellular Roles and Expression Landscape The expression profile of [FADD](/details-gene/8772) underscores its importance in tissues with high turnover rates and those involved in host defense. **Overall**, the gene shows the highest significance in ectodermal and epithelial lineages. It is a defining marker for `[melanocyte of skin](/details-cell/CL1000458)` (CSI: 7.50), `[basal cell of epidermis](/details-cell/CL0002187)` (CSI: 4.58), and `[suprabasal keratinocyte](/details-cell/CL4033013)` (CSI: 2.66), which is consistent with its role in mediating apoptosis in response to stimuli like UV radiation or cellular damage. Its high significance in `[neural crest cell](/details-cell/CL0011012)` (CSI: 3.46) and `[peripheral nervous system neuron](/details-cell/CL2000032)` (CSI: 2.70) suggests a role in developmental programmed cell death and neuronal homeostasis. Furthermore, [FADD](/details-gene/8772) is significantly expressed in various epithelial cells, including `[duct epithelial cell](/details-cell/CL0000068)` (CSI: 2.82) and `[intestinal epithelial cell](/details-cell/CL0002563)` (CSI: 2.56), highlighting its function in maintaining the integrity of mucosal and glandular barriers. The gene also shows relevance in progenitor populations such as `[stem cell](/details-cell/CL0000034)` (CSI: 2.30) and `[common myeloid progenitor](/details-cell/CL0000049)` (CSI: 2.08), as well as in immune cells like the `[cytotoxic T cell](/details-cell/CL0000910)` (CSI: 2.20), consistent with its function in immune regulation and activation-induced cell death. ## Pathways and Molecular Function [FADD](/details-gene/8772) functions as a canonical adaptor protein in programmed cell death and inflammation. Its molecular function is dominated by its ability to form protein-protein interactions via its specialized domains, as annotated by GO terms like '[Death receptor binding](/details-ontology/GO:0005123)', '[Death effector domain binding](/details-ontology/GO:0035877)', and '[Caspase binding](/details-ontology/GO:0089720)'. Biologically, [FADD](/details-gene/8772) is a cornerstone of the '[Extrinsic apoptotic signaling pathway via death domain receptors](/details-ontology/GO:0008625)', a process critical for eliminating unwanted or damaged cells. It is essential for the assembly of the '[Cd95 death-inducing signaling complex](/details-ontology/GO:0031265)' and the subsequent '[Activation of cysteine-type endopeptidase activity](/details-ontology/GO:0097202)'. This is corroborated by its central position in Reactome pathways such as '[Death receptor signaling](/details-reactome/R-HSA-73887)' and '[Apoptosis](/details-reactome/R-HSA-109581)'. Beyond apoptosis, [FADD](/details-gene/8772) is also implicated in the '[Innate immune response](/details-ontology/GO:0045087)' and '[Necroptotic signaling pathway](/details-ontology/GO:0097527)'. It participates in several Toll-like receptor cascades, including '[Toll like receptor 3 (tlr3) cascade](/details-reactome/R-HSA-168164)' and '[Toll like receptor 4 (tlr4) cascade](/details-reactome/R-HSA-166016)', where it can modulate NF-kappaB activation and interferon responses. This dual role in orchestrating both cell death and survival/inflammatory signals places [FADD](/details-gene/8772) at a critical decision point in the cellular response to stress and pathogens. ## Research Directions The widespread and critical role of [FADD](/details-gene/8772) in apoptosis and immunity presents several avenues for future investigation, particularly concerning its function in tissue-specific pathologies like cancer and inflammatory diseases. ### Proposed Hypotheses: 1. **Hypothesis 1:** Given its high significance in `[melanocyte of skin](/details-cell/CL1000458)` and its central pro-apoptotic function, downregulation or mutation of [FADD](/details-gene/8772) may be a key mechanism for melanoma cells to evade apoptosis, thereby promoting tumorigenesis and resistance to therapies that rely on inducing cell death. 2. **Hypothesis 2:** In barrier tissues like the intestine, [FADD](/details-gene/8772) may function as a rheostat that determines the cellular outcome following pathogen recognition. Depending on the signaling context, it may either trigger apoptosis to eliminate infected `[intestinal epithelial cell](/details-cell/CL0002563)`s or pivot towards NF-kappaB-mediated inflammation, with dysregulation contributing to inflammatory bowel disease. ### Key Experimental Approach: To test the role of [FADD](/details-gene/8772) in melanoma chemoresistance (Hypothesis 1), an experiment could be designed as follows: - **Objective:** Determine if [FADD](/details-gene/8772) expression level dictates the sensitivity of melanoma cells to BRAF inhibitors. - **Method:** A panel of human melanoma cell lines with varying endogenous [FADD](/details-gene/8772) levels would be utilized. [FADD](/details-gene/8772) expression would be further manipulated using CRISPR-Cas9 knockout and lentiviral overexpression systems. These engineered cell lines would then be treated with a clinically relevant BRAF inhibitor (e.g., vemurafenib). - **Readouts:** The effects would be quantified by measuring apoptosis rates via flow cytometry for Annexin V/PI staining and by assessing long-term cell survival using colony formation assays. This would directly test whether loss of [FADD](/details-gene/8772) confers a survival advantage against therapy-induced apoptosis. ### Therapeutic Potential: As a central initiator of apoptosis, [FADD](/details-gene/8772) represents a compelling, albeit challenging, therapeutic target. The primary strategy would involve **activation** of the [FADD](/details-gene/8772)-mediated apoptotic pathway in cancer cells. This could potentially be achieved with small molecules designed to promote the oligomerization of [FADD](/details-gene/8772) or stabilize its interaction with procaspase-8 within the DISC, thereby lowering the threshold for apoptosis induction. Such an approach could be particularly effective as a combination therapy to resensitize tumors that have developed resistance to conventional treatments by upregulating anti-apoptotic proteins. However, the systemic activation of [FADD](/details-gene/8772) carries a high risk of toxicity, necessitating highly targeted delivery systems (e.g., antibody-drug conjugates) to ensure cancer cell-specific activity.

Genular Protein ID: 2089566895

Symbol: FADD_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q13158 Q14866 Q6IBR4

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CORUM 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 9 EMDB 1 Ensembl 1 EvolutionaryTrace 1 GO 57 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 5 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 MetOSite 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PDB 12 PDBsum 12 PIR 1 PIRSF 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 14 RefSeq 1 SIGNOR 1 SMART 2 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: 7538907

Title: FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.

PubMed ID: 7538907

DOI: 10.1016/0092-8674(95)90071-3

PubMed ID: 7536190

Title: A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain.

PubMed ID: 7536190

DOI: 10.1074/jbc.270.14.7795

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: 9184224

Title: FLICE is activated by association with the CD95 death-inducing signaling complex (DISC).

PubMed ID: 9184224

DOI: 10.1093/emboj/16.10.2794

PubMed ID: 10442631

Title: PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.

PubMed ID: 10442631

DOI: 10.1038/sj.onc.1202831

PubMed ID: 10825539

Title: LRDD, a novel leucine rich repeat and death domain containing protein.

PubMed ID: 10825539

DOI: 10.1016/s0167-4838(00)00029-7

PubMed ID: 11034606

Title: FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits Fas-mediated Jun NH2-terminal kinase activation.

PubMed ID: 11034606

DOI: 10.1084/jem.192.8.1165

PubMed ID: 11259186

Title: Molluscum contagiosum virus inhibitors of apoptosis: The MC159 v-FLIP protein blocks Fas-induced activation of procaspases and degradation of the related MC160 protein.

PubMed ID: 11259186

DOI: 10.1006/viro.2001.0834

PubMed ID: 12702765

Title: Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis.

PubMed ID: 12702765

DOI: 10.1073/pnas.0431215100

PubMed ID: 16127453

Title: IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.

PubMed ID: 16127453

DOI: 10.1038/ni1243

PubMed ID: 18846110

Title: Identification of an antiapoptotic protein complex at death receptors.

PubMed ID: 18846110

DOI: 10.1038/cdd.2008.124

PubMed ID: 18632871

Title: The interaction between human papillomavirus type 16 and FADD is mediated by a novel E6 binding domain.

PubMed ID: 18632871

DOI: 10.1128/jvi.00538-08

PubMed ID: 19413330

Title: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.

PubMed ID: 19413330

DOI: 10.1021/ac9004309

PubMed ID: 19690332

Title: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.

PubMed ID: 19690332

DOI: 10.1126/scisignal.2000007

PubMed ID: 21109225

Title: Whole-exome-sequencing-based discovery of human FADD deficiency.

PubMed ID: 21109225

DOI: 10.1016/j.ajhg.2010.10.028

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 23955153

Title: Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains.

PubMed ID: 23955153

DOI: 10.1038/nature12436

PubMed ID: 24025841

Title: A type III effector antagonizes death receptor signalling during bacterial gut infection.

PubMed ID: 24025841

DOI: 10.1038/nature12524

PubMed ID: 28069818

Title: SseK1 and SseK3 type III secretion system effectors inhibit NF-kappaB signaling and necroptotic cell death in salmonella-infected macrophages.

PubMed ID: 28069818

DOI: 10.1128/iai.00010-17

PubMed ID: 28860194

Title: The bacterial arginine glycosyltransferase effector NleB preferentially modifies Fas-associated death domain protein (FADD).

PubMed ID: 28860194

DOI: 10.1074/jbc.m117.805036

PubMed ID: 9582077

Title: NMR structure and mutagenesis of the FADD (Mort1) death-effector domain.

PubMed ID: 9582077

DOI: 10.1038/31972

PubMed ID: 10964568

Title: The three-dimensional solution structure and dynamic properties of the human FADD death domain.

PubMed ID: 10964568

DOI: 10.1006/jmbi.2000.4011

PubMed ID: 16762833

Title: The structure of FADD and its mode of interaction with procaspase-8.

PubMed ID: 16762833

DOI: 10.1016/j.molcel.2006.04.018

PubMed ID: 19118384

Title: The Fas-FADD death domain complex structure unravels signalling by receptor clustering.

PubMed ID: 19118384

DOI: 10.1038/nature07606

PubMed ID: 20935634

Title: The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations.

PubMed ID: 20935634

DOI: 10.1038/nsmb.1920

PubMed ID: 30979585

Title: Structural and functional insights into host death domains inactivation by the bacterial arginine GlcNAcyltransferase effector.

PubMed ID: 30979585

DOI: 10.1016/j.molcel.2019.03.028

Sequence Information:

  • Length: 208
  • Mass: 23279
  • Checksum: 0E65E2F852E83507
  • Sequence:
    • MDPFLVLLHS VSSSLSSSEL TELKFLCLGR VGKRKLERVQ SGLDLFSMLL EQNDLEPGHT 
ELLRELLASL RRHDLLRRVD DFEAGAAAGA APGEEDLCAA FNVICDNVGK DWRRLARQLK 
VSDTKIDSIE DRYPRNLTER VRESLRIWKN TEKENATVAH LVGALRSCQM NLVADLVQEV 
QQARDLQNRS GAMSPMSWNS DASTSEAS