Tumor necrosis factor alpha (TNF-alpha) is a signaling molecule that interacts with one of two receptors on cells targeted for apoptosis. The apoptotic signal is transduced inside these cells by cytoplasmic adaptor proteins. The protein encoded by this gene is a death domain-containing adaptor protein that interacts with the death domain of TNF-alpha receptor 1 to activate mito... See more...

Aliases for MADD Gene

Aliases for MADD Gene

  • MAP Kinase Activating Death Domain 2 3 5
  • Differentially Expressed In Normal And Neoplastic Cells 3 4
  • MAP Kinase-Activating Death Domain Protein 3 4
  • Insulinoma Glucagonoma Clone 20 3 4
  • Rab3 GDP/GTP Exchange Factor 3 4
  • DENN 3 4
  • IG20 3 4
  • MAP-Kinase Activating Death Domain 2
  • KIAA0358 4
  • RAB3GEP 3

External Ids for MADD Gene

Previous GeneCards Identifiers for MADD Gene

  • GC11P049230
  • GC11P048168
  • GC11P047322
  • GC11P047255
  • GC11P047247
  • GC11P046990

Summaries for MADD Gene

Entrez Gene Summary for MADD Gene

  • Tumor necrosis factor alpha (TNF-alpha) is a signaling molecule that interacts with one of two receptors on cells targeted for apoptosis. The apoptotic signal is transduced inside these cells by cytoplasmic adaptor proteins. The protein encoded by this gene is a death domain-containing adaptor protein that interacts with the death domain of TNF-alpha receptor 1 to activate mitogen-activated protein kinase (MAPK) and propagate the apoptotic signal. It is membrane-bound and expressed at a higher level in neoplastic cells than in normal cells. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

GeneCards Summary for MADD Gene

MADD (MAP Kinase Activating Death Domain) is a Protein Coding gene. Diseases associated with MADD include Diastolic Heart Failure and Charcot-Marie-Tooth Disease, Type 4B3. Among its related pathways are TNF signaling (REACTOME) and RAB GEFs exchange GTP for GDP on RABs. Gene Ontology (GO) annotations related to this gene include Rab guanyl-nucleotide exchange factor activity and death receptor binding.

UniProtKB/Swiss-Prot Summary for MADD Gene

  • Plays a significant role in regulating cell proliferation, survival and death through alternative mRNA splicing. Isoform 5 shows increased cell proliferation and isoform 2 shows decreased. Converts GDP-bound inactive form of RAB3A, RAB3C and RAB3D to the GTP-bound active forms. Component of the TNFRSF1A signaling complex: MADD links TNFRSF1A with MAP kinase activation. Plays an important regulatory role in physiological cell death (TNF-alpha-induced, caspase-mediated apoptosis); isoform 1 is susceptible to inducing apoptosis, isoform 5 is resistant and isoform 3 and isoform 4 have no effect.

Gene Wiki entry for MADD Gene

Additional gene information for MADD Gene

No data available for CIViC Summary , Tocris Summary , PharmGKB "VIP" Summary , Rfam classification and piRNA Summary for MADD Gene

Genomics for MADD Gene

GeneHancer (GH) Regulatory Elements for MADD Gene

Promoters and enhancers for MADD Gene
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around MADD on UCSC Golden Path with GeneCards custom track

Cistromic (ChIP-Seq) regulation report from SPP (The Signaling Pathways Project) for MADD

Top Transcription factor binding sites by QIAGEN in the MADD gene promoter:
  • AP-2alpha

Genomic Locations for MADD Gene

Genomic Locations for MADD Gene
chr11:47,269,161-47,330,031
(GRCh38/hg38)
Size:
60,871 bases
Orientation:
Plus strand
chr11:47,290,712-47,351,582
(GRCh37/hg19)
Size:
60,871 bases
Orientation:
Plus strand

Genomic View for MADD Gene

Genes around MADD on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
MADD Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for MADD Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for MADD Gene

Proteins for MADD Gene

  • Protein details for MADD Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    Q8WXG6-MADD_HUMAN
    Recommended name:
    MAP kinase-activating death domain protein
    Protein Accession:
    Q8WXG6
    Secondary Accessions:
    • A8K8S7
    • B5MEE5
    • D3DQR4
    • O15065
    • O15293
    • Q15732
    • Q15741
    • Q8IWD7
    • Q8WXG3
    • Q8WXG4
    • Q8WXG5
    • Q8WZ63

    Protein attributes for MADD Gene

    Size:
    1647 amino acids
    Molecular mass:
    183303 Da
    Quaternary structure:
    • Interacts with the death domain of TNFRSF1A through its own death domain. Interacts with PIDD1. Interacts with YWHAZ (PubMed:16959763).
    Miscellaneous:
    • Overexpression of MADD activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Expression of the MADD death domain stimulates both the ERK and c-JUN N-terminal kinase MAP kinases and induces the phosphorylation of cytosolic phospholipase A2.
    SequenceCaution:
    • Sequence=BAA20814.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

    Alternative splice isoforms for MADD Gene

neXtProt entry for MADD Gene

Post-translational modifications for MADD Gene

  • Modification sites at PhosphoSitePlus
  • Modification sites at neXtProt

Other Protein References for MADD Gene

ENSEMBL proteins:
REFSEQ proteins:

No data available for DME Specific Peptides for MADD Gene

Domains & Families for MADD Gene

Gene Families for MADD Gene

HGNC:
Human Protein Atlas (HPA):
  • Predicted intracellular proteins
  • Predicted membrane proteins

Protein Domains for MADD Gene

Suggested Antigen Peptide Sequences for MADD Gene

GenScript: Design optimal peptide antigens:
  • Rab3 GDP/GTP exchange factor (MADD_HUMAN)
  • DENN protein (Q7KYV8_HUMAN)

Graphical View of Domain Structure for InterPro Entry

Q8WXG6

UniProtKB/Swiss-Prot:

MADD_HUMAN :
  • Belongs to the MADD family.
Family:
  • Belongs to the MADD family.
genes like me logo Genes that share domains with MADD: view

Function for MADD Gene

Molecular function for MADD Gene

UniProtKB/Swiss-Prot Function:
Plays a significant role in regulating cell proliferation, survival and death through alternative mRNA splicing. Isoform 5 shows increased cell proliferation and isoform 2 shows decreased. Converts GDP-bound inactive form of RAB3A, RAB3C and RAB3D to the GTP-bound active forms. Component of the TNFRSF1A signaling complex: MADD links TNFRSF1A with MAP kinase activation. Plays an important regulatory role in physiological cell death (TNF-alpha-induced, caspase-mediated apoptosis); isoform 1 is susceptible to inducing apoptosis, isoform 5 is resistant and isoform 3 and isoform 4 have no effect.
GENATLAS Biochemistry:
Map kinase-activating death domain protein homolog and similar to C elegans AEX3,differentially expressed in normal and neoplastic cell,linkingTNFR1 with MAP kinase activation and arachidonic acid release and provide further insight into the mechanisms by which TNF exerts its pleiotropic effects

Phenotypes From GWAS Catalog for MADD Gene

Gene Ontology (GO) - Molecular Function for MADD Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005085 guanyl-nucleotide exchange factor activity IEA --
GO:0005123 death receptor binding TAS 9115275
GO:0005515 protein binding IPI 9115275
GO:0017112 Rab guanyl-nucleotide exchange factor activity TAS --
GO:0030295 protein kinase activator activity TAS 9115275
genes like me logo Genes that share ontologies with MADD: view
genes like me logo Genes that share phenotypes with MADD: view

Animal Models for MADD Gene

MGI Knock Outs for MADD:

Animal Model Products

CRISPR Products

miRNA for MADD Gene

Clone Products

No data available for Enzyme Numbers (IUBMB) , Human Phenotype Ontology , Transcription Factor Targets and HOMER Transcription for MADD Gene

Localization for MADD Gene

Subcellular locations from UniProtKB/Swiss-Prot for MADD Gene

Membrane. Cytoplasm.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for MADD gene
Compartment Confidence
plasma membrane 5
cytosol 5
extracellular 2
cytoskeleton 2
mitochondrion 2
nucleus 2
endosome 2
lysosome 2
golgi apparatus 2
peroxisome 1
endoplasmic reticulum 1

Subcellular locations from the

Human Protein Atlas (HPA)
  • Cytosol (3)
  • Plasma membrane (2)
See all subcellular structures

Gene Ontology (GO) - Cellular Components for MADD Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005737 cytoplasm TAS 8988362
GO:0005829 cytosol IDA,TAS --
GO:0005886 plasma membrane IDA --
GO:0016020 membrane IEA --
GO:0016021 integral component of membrane IDA 8988362
genes like me logo Genes that share ontologies with MADD: view

Pathways & Interactions for MADD Gene

genes like me logo Genes that share pathways with MADD: view

Gene Ontology (GO) - Biological Process for MADD Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000187 activation of MAPK activity IMP 9115275
GO:0006915 apoptotic process IEA --
GO:0007166 cell surface receptor signaling pathway TAS 9115275
GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway TAS --
GO:0032483 regulation of Rab protein signal transduction IDA,IBA 20937701
genes like me logo Genes that share ontologies with MADD: view

No data available for SIGNOR curated interactions for MADD Gene

Drugs & Compounds for MADD Gene

(4) Drugs for MADD Gene - From: HMDB and Novoseek

Name Status Disease Links Group Role Mechanism of Action Clinical Trials
Guanosine diphosphate Experimental Pharma 0
Guanosine triphosphate Experimental Pharma 0

(2) Additional Compounds for MADD Gene - From: Novoseek

Name Synonyms Role CAS Number PubChem IDs PubMed IDs
genes like me logo Genes that share compounds with MADD: view

Transcripts for MADD Gene

mRNA/cDNA for MADD Gene

97 REFSEQ mRNAs :
17 NCBI additional mRNA sequence :
23 Ensembl transcripts including schematic representations, and UCSC links to gene/alias where relevant :

CRISPR Products

Clone Products

Alternative Splicing Database (ASD) splice patterns (SP) for MADD Gene

ExUns: 1 ^ 2 ^ 3 ^ 4a · 4b · 4c ^ 5 ^ 6 ^ 7a · 7b · 7c · 7d ^ 8a · 8b ^ 9a · 9b ^ 10a · 10b ^ 11 ^ 12 ^ 13 ^ 14 ^ 15 ^ 16 ^ 17a · 17b ^
SP1: - - - - - -
SP2: - -
SP3: - - - - - - -
SP4: - - - - - -
SP5: - - - - - - -
SP6: - - - - - - -
SP7: - - -
SP8: - -
SP9: - - - - - - -
SP10:
SP11:
SP12:
SP13:
SP14: -
SP15:
SP16: - - - - - - - - - - -
SP17:
SP18: - - - -
SP19:
SP20: - -
SP21:

ExUns: 18a · 18b ^ 19 ^ 20 ^ 21 ^ 22a · 22b ^ 23a · 23b · 23c · 23d ^ 24 ^ 25 ^ 26 ^ 27a · 27b ^ 28a · 28b ^ 29 ^ 30 ^ 31 ^ 32 ^ 33 ^ 34 ^ 35 ^ 36 ^
SP1: -
SP2: -
SP3: - - -
SP4: - - -
SP5: - - - -
SP6: - - - -
SP7: - - - -
SP8: - - - -
SP9: - - - -
SP10: - -
SP11: -
SP12:
SP13:
SP14: - - -
SP15: -
SP16:
SP17:
SP18:
SP19:
SP20:
SP21:

ExUns: 37 ^ 38a · 38b ^ 39a · 39b ^ 40a · 40b
SP1: - -
SP2: - - -
SP3: - -
SP4: - -
SP5: - -
SP6: - -
SP7: - -
SP8: - -
SP9: - - -
SP10:
SP11:
SP12:
SP13:
SP14:
SP15:
SP16:
SP17:
SP18:
SP19:
SP20:
SP21:

Relevant External Links for MADD Gene

GeneLoc Exon Structure for
MADD

Expression for MADD Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and SAGE for MADD Gene

mRNA expression in embryonic tissues and stem cells from LifeMap Discovery

Protein differential expression in normal tissues from HIPED for MADD Gene

This gene is overexpressed in Cervix (15.5), Peripheral blood mononuclear cells (11.8), Plasma (11.0), Frontal cortex (9.8), and Brain (8.1).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, MaxQB, and MOPED for MADD Gene



Protein tissue co-expression partners for MADD Gene

- Elite partner

Transcriptomic regulation report from SPP (The Signaling Pathways Project) for MADD

SOURCE GeneReport for Unigene cluster for MADD Gene:

Hs.82548

mRNA Expression by UniProt/SwissProt for MADD Gene:

Q8WXG6-MADD_HUMAN
Tissue specificity: Highly expressed in fetal brain and kidney; adult testis, ovary, brain and heart. Isoform 5 is constitutively expressed in all tissues. Isoform 7 is expressed in fetal liver and in several cancer cell lines.

Evidence on tissue expression from TISSUES for MADD Gene

  • Nervous system(4.6)
genes like me logo Genes that share expression patterns with MADD: view

No data available for mRNA differential expression in normal tissues and Phenotype-based relationships between genes and organs from Gene ORGANizer for MADD Gene

Orthologs for MADD Gene

This gene was present in the common ancestor of animals.

Orthologs for MADD Gene

Organism Taxonomy Gene Similarity Type Details
chimpanzee
(Pan troglodytes)
Mammalia MADD 31 30
  • 99.66 (n)
OneToOne
dog
(Canis familiaris)
Mammalia MADD 31 30
  • 93.1 (n)
OneToOne
mouse
(Mus musculus)
Mammalia Madd 17 31 30
  • 89.74 (n)
cow
(Bos Taurus)
Mammalia MADD 31 30
  • 89.41 (n)
OneToOne
rat
(Rattus norvegicus)
Mammalia Madd 30
  • 89.35 (n)
oppossum
(Monodelphis domestica)
Mammalia MADD 31
  • 89 (a)
OneToOne
platypus
(Ornithorhynchus anatinus)
Mammalia -- 31
  • 88 (a)
OneToMany
-- 31
  • 78 (a)
OneToMany
-- 31
  • 72 (a)
OneToMany
chicken
(Gallus gallus)
Aves MADD 31 30
  • 76.59 (n)
OneToOne
lizard
(Anolis carolinensis)
Reptilia MADD 31
  • 82 (a)
OneToOne
tropical clawed frog
(Silurana tropicalis)
Amphibia madd 30
  • 73.26 (n)
African clawed frog
(Xenopus laevis)
Amphibia Xl.1613 30
zebrafish
(Danio rerio)
Actinopterygii madd 31 30
  • 70.17 (n)
OneToOne
fruit fly
(Drosophila melanogaster)
Insecta rab3-GEF 31 32 30
  • 56.87 (n)
OneToOne
African malaria mosquito
(Anopheles gambiae)
Insecta AgaP_AGAP000630 30
  • 56.03 (n)
worm
(Caenorhabditis elegans)
Secernentea aex-3 31 32 30
  • 53.74 (n)
OneToOne
sea squirt
(Ciona savignyi)
Ascidiacea -- 31
  • 39 (a)
OneToOne
Cin.11493 30
sea squirt
(Ciona intestinalis)
Ascidiacea Cin.11493 30
Species where no ortholog for MADD was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Ashbya gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • Alicante grape (Vitis vinifera)
  • alpha proteobacteria (Wolbachia pipientis)
  • amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • baker's yeast (Saccharomyces cerevisiae)
  • barley (Hordeum vulgare)
  • beta proteobacteria (Neisseria meningitidis)
  • bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • common water flea (Daphnia pulex)
  • corn (Zea mays)
  • E. coli (Escherichia coli)
  • filamentous fungi (Aspergillus nidulans)
  • Firmicute bacteria (Streptococcus pneumoniae)
  • fission yeast (Schizosaccharomyces pombe)
  • green algae (Chlamydomonas reinhardtii)
  • honey bee (Apis mellifera)
  • K. lactis yeast (Kluyveromyces lactis)
  • loblloly pine (Pinus taeda)
  • malaria parasite (Plasmodium falciparum)
  • medicago trunc (Medicago Truncatula)
  • moss (Physcomitrella patens)
  • orangutan (Pongo pygmaeus)
  • pig (Sus scrofa)
  • rainbow trout (Oncorhynchus mykiss)
  • rice (Oryza sativa)
  • rice blast fungus (Magnaporthe grisea)
  • schistosome parasite (Schistosoma mansoni)
  • sea anemone (Nematostella vectensis)
  • sea urchin (Strongylocentrotus purpuratus)
  • sorghum (Sorghum bicolor)
  • soybean (Glycine max)
  • stem rust fungus (Puccinia graminis)
  • sugarcane (Saccharum officinarum)
  • thale cress (Arabidopsis thaliana)
  • tomato (Lycopersicon esculentum)
  • toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • wheat (Triticum aestivum)

Evolution for MADD Gene

ENSEMBL:
Gene Tree for MADD (if available)
TreeFam:
Gene Tree for MADD (if available)
Aminode:
Evolutionary constrained regions (ECRs) for MADD: view image

Paralogs for MADD Gene

(3) SIMAP similar genes for MADD Gene using alignment to 6 proteins:

  • MADD_HUMAN
  • C9J6B0_HUMAN
  • C9JLZ9_HUMAN
  • C9JM97_HUMAN
  • C9K0L0_HUMAN
  • F8W8U2_HUMAN
genes like me logo Genes that share paralogs with MADD: view

No data available for Paralogs for MADD Gene

Variants for MADD Gene

Sequence variations, with clinical significance, from ClinVar and Humsavar, with links to dbSNP for MADD Gene

SNP ID Clinical significance and condition Chr 11 pos Variation AA Info Type
709997 Benign: not provided 47,274,631(+) C/A MISSENSE_VARIANT,NON_CODING_TRANSCRIPT_VARIANT,FIVE_PRIME_UTR_VARIANT,INTRON_VARIANT
720869 Benign: not provided 47,281,614(+) A/G MISSENSE_VARIANT,NON_CODING_TRANSCRIPT_VARIANT
723531 Benign: not provided 47,282,913(+) T/A NON_CODING_TRANSCRIPT_VARIANT,SYNONYMOUS_VARIANT
724274 Likely Benign: not provided 47,293,974(+) T/G NON_CODING_TRANSCRIPT_VARIANT,SYNONYMOUS_VARIANT
768445 Benign: not provided 47,279,082(+) A/G INTRON_VARIANT

Additional dbSNP identifiers (rs#s) for MADD Gene

Structural Variations from Database of Genomic Variants (DGV) for MADD Gene

Variant ID Type Subtype PubMed ID
nsv1145519 CNV deletion 24896259
nsv825870 CNV gain 20364138
nsv832141 CNV loss 17160897

Variation tolerance for MADD Gene

Residual Variation Intolerance Score: 1.72% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 9.53; 88.86% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for MADD Gene

Human Gene Mutation Database (HGMD)
MADD
SNPedia medical, phenotypic, and genealogical associations of SNPs for
MADD

SNP Genotyping and Copy Number Assay Products

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for MADD Gene

Disorders for MADD Gene

MalaCards: The human disease database

(5) MalaCards diseases for MADD Gene - From: DISEASES and GeneCards

- elite association - COSMIC cancer census association via MalaCards
Search MADD in MalaCards View complete list of genes associated with diseases

Additional Disease Information for MADD

Genetic Association Database
(GAD)
Human Genome Epidemiology Navigator
(HuGE)
ATLAS of Genetics and Cytogenetics in Oncology and Haematology
genes like me logo Genes that share disorders with MADD: view

No data available for UniProtKB/Swiss-Prot and Genatlas for MADD Gene

Publications for MADD Gene

  1. The human DENN gene: genomic organization, alternative splicing, and localization to chromosome 11p11.21-p11.22. (PMID: 9796103) Chow VT … Lim D (Genome 1998) 2 3 4 23 54
  2. IG20, in contrast to DENN-SV, (MADD splice variants) suppresses tumor cell survival, and enhances their susceptibility to apoptosis and cancer drugs. (PMID: 14716293) Efimova EV … Prabhakar BS (Oncogene 2004) 3 4 23 54
  3. Contrasting effects of IG20 and its splice isoforms, MADD and DENN-SV, on tumor necrosis factor alpha-induced apoptosis and activation of caspase-8 and -3. (PMID: 11577081) Al-Zoubi AM … Prabhakar BS (The Journal of biological chemistry 2001) 3 4 23 54
  4. MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase. (PMID: 9115275) Schievella AR … Lin LL (The Journal of biological chemistry 1997) 2 3 4 54
  5. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. (PMID: 21873549) Strawbridge RJ … Florez JC (Diabetes 2011) 3 41 54

Products for MADD Gene