Reviewed,
UniProtKB/Swiss-Prot Q8WXG6 (MADD_HUMAN)
Last modified
November 24, 2009.
Version 42.
History...
Clusters with 100%,
90%,
50% identity |
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Names and origin
| Protein names | Recommended name: MAP kinase-activating death domain protein Alternative name(s): Differentially expressed in normal and neoplastic cells Insulinoma glucagonoma clone 20 Rab3 GDP/GTP exchange factor | ||||
| Gene names |
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| Organism | Homo sapiens (Human) [Complete proteome] | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 1647 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is further processed into a mature form. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| 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. Ref.2 Ref.4 Ref.7 Ref.8 Ref.9 |
| Subunit structure | Interacts with the death domain of TNFRSF1A through its own death domain. Ref.2 Ref.4 |
| Subcellular location | |
| 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. Ref.8 Ref.1 Ref.3 |
| 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. Ref.2 |
| Sequence similarities | Belongs to the MADD family. Contains 1 dDENN domain. Contains 1 death domain. Contains 1 DENN domain. Contains 1 uDENN domain. |
Ontologies
Alternative products
| This entry describes 7 isoforms produced by alternative splicing. [Align] [Select] | ||||||
| Isoform 1 Ref.4 (identifier: Q8WXG6-1) Also known as: IG20; IG20-FL; This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. | ||||||
| Isoform 2 Ref.4 (identifier: Q8WXG6-2) Also known as: IG20; IG20-PA; IG20-PASV; The sequence of this isoform differs from the canonical sequence as follows: 1121-1139: ELWNKHQEVKKQKALEKQR → G 1291-1311: Missing. | ||||||
| Isoform 3 Ref.2 Ref.1 Ref.3 (identifier: Q8WXG6-3) Also known as: DENN; IG20-SV1; MADD; The sequence of this isoform differs from the canonical sequence as follows: 885-904: Missing. 1121-1139: ELWNKHQEVKKQKALEKQR → G 1291-1311: Missing. | ||||||
| Isoform 4 Ref.4 Ref.1 Ref.3 (identifier: Q8WXG6-4) Also known as: IG20-SV2; The sequence of this isoform differs from the canonical sequence as follows: 762-804: Missing. 1121-1139: ELWNKHQEVKKQKALEKQR → G 1291-1311: Missing. | ||||||
| Isoform 5 Ref.4 Ref.6 (identifier: Q8WXG6-5) Also known as: DENN-SV; IG20-SV3; The sequence of this isoform differs from the canonical sequence as follows: 762-804: Missing. 885-904: Missing. 1121-1139: ELWNKHQEVKKQKALEKQR → G 1291-1311: Missing. | ||||||
| Isoform 6 Ref.4 (identifier: Q8WXG6-6) Also known as: IG20-SV4; The sequence of this isoform differs from the canonical sequence as follows: 762-804: Missing. 885-904: Missing. 1121-1139: ELWNKHQEVKKQKALEKQR → G 1291-1311: Missing. 1575-1582: VFIELNHI → FLKLKKW 1583-1647: Missing. | ||||||
| Isoform 7 Ref.5 (identifier: Q8WXG6-7) The sequence of this isoform differs from the canonical sequence as follows: 1575-1582: VFIELNHI → FLKLKKW 1583-1647: Missing. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Initiator methionine | 1 | 1 | Removed By similarity UniProtKB O08873 | ||||||
| Chain | 2 – 1647 | 1646 | MAP kinase-activating death domain protein UniProtKB O08873 | PRO_0000278138 | |||||
Regions | |||||||||
| Transmembrane | 336 – 356 | 21 | Potential | ||||||
| Transmembrane | 366 – 386 | 21 | Potential | ||||||
| Domain | 8 – 104 | 97 | uDENN | ||||||
| Domain | 172 – 402 | 231 | DENN | ||||||
| Domain | 485 – 558 | 74 | dDENN | ||||||
| Domain | 1340 – 1415 | 76 | Death | ||||||
| Compositional bias | 1157 – 1250 | 94 | Ser-rich | ||||||
Amino acid modifications | |||||||||
| Modified residue | 818 | 1 | Phosphoserine Ref.10 | ||||||
| Modified residue | 820 | 1 | Phosphoserine Ref.10 | ||||||
| Modified residue | 921 | 1 | Phosphoserine Ref.10 | ||||||
| Modified residue | 1059 | 1 | Phosphoserine By similarity UniProtKB Q80U28 | ||||||
| Modified residue | 1061 | 1 | Phosphothreonine By similarity UniProtKB Q80U28 | ||||||
| Modified residue | 1237 | 1 | Phosphothreonine | ||||||
| Modified residue | 1270 | 1 | Phosphoserine Ref.10 | ||||||
Natural variations | |||||||||
| Alternative sequence | 762 – 804 | 43 | Missing in isoform 4, isoform 5 and isoform 6. Ref.4 Ref.1 Ref.3 Ref.6 | VSP_052293 | |||||
| Alternative sequence | 885 – 904 | 20 | Missing in isoform 3, isoform 5 and isoform 6. Ref.2 Ref.4 Ref.1 Ref.3 Ref.6 | VSP_052294 | |||||
| Alternative sequence | 1121 – 1139 | 19 | ELWNK…LEKQR → G in isoform 2, isoform 3, isoform 4, isoform 5 and isoform 6. Ref.2 Ref.4 Ref.1 Ref.3 Ref.6 | VSP_052295 | |||||
| Alternative sequence | 1291 – 1311 | 21 | Missing in isoform 2, isoform 3, isoform 4, isoform 5 and isoform 6. Ref.2 Ref.4 Ref.1 Ref.3 Ref.6 | VSP_052296 | |||||
| Alternative sequence | 1575 – 1582 | 8 | VFIELNHI → FLKLKKW in isoform 6 and isoform 7. Ref.4 Ref.5 | VSP_052297 | |||||
| Alternative sequence | 1583 – 1647 | 65 | Missing in isoform 6 and isoform 7. Ref.4 Ref.5 | VSP_052298 | |||||
| Natural variant | 696 | 1 | P → T: dbSNP rs17854007. Ref.6 | VAR_030666 | |||||
| Natural variant | 751 | 1 | V → M: dbSNP rs1051006. Ref.2 | VAR_030667 | |||||
| Natural variant | 765 | 1 | R → Q: dbSNP rs3736101. | VAR_051148 | |||||
| Natural variant | 968 | 1 | R → G: dbSNP rs17854008. Ref.6 | VAR_030668 | |||||
| Natural variant | 1040 | 1 | L → F: dbSNP rs17854009. Ref.6 | VAR_030669 | |||||
| Natural variant | 1518 | 1 | L → P: dbSNP rs34534575. | VAR_051149 | |||||
Experimental info | |||||||||
| Sequence conflict | 108 | 1 | E → G in AAL40265. Ref.4 | ||||||
| Sequence conflict | 108 | 1 | E → G in AAL40266. Ref.4 | ||||||
| Sequence conflict | 108 | 1 | E → G in AAL40267. Ref.4 | ||||||
| Sequence conflict | 108 | 1 | E → G in AAL40268. Ref.4 | ||||||
| Sequence conflict | 108 | 1 | E → G in AAL35261. Ref.4 | ||||||
| Sequence conflict | 145 | 1 | L → F in AAL40265. Ref.4 | ||||||
| Sequence conflict | 145 | 1 | L → F in AAL40266. Ref.4 | ||||||
| Sequence conflict | 145 | 1 | L → F in AAL40267. Ref.4 | ||||||
| Sequence conflict | 145 | 1 | L → F in AAL40268. Ref.4 | ||||||
| Sequence conflict | 145 | 1 | L → F in AAL35261. Ref.4 | ||||||
| Sequence conflict | 312 | 1 | V → L in AAL40265. Ref.4 | ||||||
| Sequence conflict | 312 | 1 | V → L in AAL40266. Ref.4 | ||||||
| Sequence conflict | 312 | 1 | V → L in AAL40267. Ref.4 | ||||||
| Sequence conflict | 312 | 1 | V → L in AAL40268. Ref.4 | ||||||
| Sequence conflict | 312 | 1 | V → L in AAL35261. Ref.4 | ||||||
| Sequence conflict | 482 | 1 | V → A in AAL40265. Ref.4 | ||||||
| Sequence conflict | 482 | 1 | V → A in AAL40266. Ref.4 | ||||||
| Sequence conflict | 482 | 1 | V → A in AAL40267. Ref.4 | ||||||
| Sequence conflict | 482 | 1 | V → A in AAL40268. Ref.4 | ||||||
| Sequence conflict | 482 | 1 | V → A in AAL35261. Ref.4 | ||||||
| Sequence conflict | 1201 | 1 | Missing in AAD12154. Ref.1 | ||||||
| Sequence conflict | 1201 | 1 | Missing in AAH40484. Ref.6 | ||||||
| Sequence conflict | 1262 | 1 | S → C in AAL40265. Ref.4 | ||||||
| Sequence conflict | 1262 | 1 | S → C in AAL40266. Ref.4 | ||||||
| Sequence conflict | 1262 | 1 | S → C in AAL40267. Ref.4 | ||||||
| Sequence conflict | 1262 | 1 | S → C in AAL40268. Ref.4 | ||||||
| Sequence conflict | 1262 | 1 | S → C in AAL35261. Ref.4 | ||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "DENN, a novel human gene differentially expressed in normal and neoplastic cells." Chow V.T.K., Lee S.S. DNA Seq. 6:263-273(1996) [PubMed: 8988362] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4), SUBCELLULAR LOCATION, TISSUE SPECIFICITY. Tissue: Fetal liver. |
| [2] | "MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase." Schievella A.R., Chen J.H., Graham J.R., Lin L.-L. J. Biol. Chem. 272:12069-12075(1997) [PubMed: 9115275] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION, INTERACTION WITH TNFRSF1A, VARIANT MET-751. |
| [3] | "The human DENN gene: genomic organization, alternative splicing, and localization to chromosome 11p11.21-p11.22." Chow V.T.K., Lim K.M., Lim D. Genome 41:543-552(1998) [PubMed: 9796103] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4), TISSUE SPECIFICITY. Tissue: Liver. |
| [4] | "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." Al-Zoubi A.M., Efimova E.V., Kaithamana S., Martinez O., El-Azami El-Idrissi M., Dogan R.E., Prabhakar B.S. J. Biol. Chem. 276:47202-47211(2001) [PubMed: 11577081] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 4; 5 AND 6), FUNCTION, INTERACTION WITH TNFRSF1A. Tissue: Insulinoma. |
| [5] | "Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro." Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 4:141-150(1997) [PubMed: 9205841] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7). Tissue: Brain. |
| [6] | "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5), VARIANTS THR-696; GLY-968 AND PHE-1040. Tissue: Testis. |
| [7] | "Antisense abrogation of DENN expression induces apoptosis of leukemia cells in vitro, causes tumor regression in vivo and alters the transcription of genes involved in apoptosis and the cell cycle." Lim K.M., Yeo W.S., Chow V.T.K. Int. J. Cancer 109:24-37(2004) [PubMed: 14735464] [Abstract] Cited for: FUNCTION. |
| [8] | "IG20, in contrast to DENN-SV, (MADD splice variants) suppresses tumor cell survival, and enhances their susceptibility to apoptosis and cancer drugs." Efimova E.V., Al-Zoubi A.M., Martinez O., Kaithamana S., Lu S., Arima T., Prabhakar B.S. Oncogene 23:1076-1087(2004) [PubMed: 14716293] [Abstract] Cited for: ALTERNATIVE SPLICING, FUNCTION, TISSUE SPECIFICITY. |
| [9] | "Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons." Del Villar K., Miller C.A. Proc. Natl. Acad. Sci. U.S.A. 101:4210-4215(2004) [PubMed: 15007167] [Abstract] Cited for: FUNCTION. |
| [10] | "A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-818; SER-820; SER-921 AND SER-1270, MASS SPECTROMETRY. |
| [11] | "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1237, MASS SPECTROMETRY. Tissue: T-cell. |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |
|---|---|
| U44953 mRNA. Translation: AAD12154.1. U77352 mRNA. Translation: AAB57735.1. AF440100 mRNA. Translation: AAL40265.1. AF440101 mRNA. Translation: AAL40266.1. AF440102 mRNA. Translation: AAL40267.1. AF440103 mRNA. Translation: AAL40268.1. AF440434 mRNA. Translation: AAL35261.1. AB002356 mRNA. Translation: BAA20814.2. Different initiation. BC040484 mRNA. Translation: AAH40484.1. | |
| IPI | IPI00103536. IPI00107843. IPI00107844. IPI00237706. IPI00292094. IPI00292095. IPI00788877. |
| RefSeq | NP_001129415.1. NP_001129416.1. NP_003673.3. NP_569826.2. NP_569827.2. NP_569828.2. NP_569829.2. NP_569830.2. NP_569831.1. NP_569832.2. |
| UniGene | Hs.524906 Hs.82548 |
3D structure databases | |
| ModBase | Search... |
Protein-protein interaction databases | |
| IntAct | Q8WXG6. 2 interactions. |
| STRING | Q8WXG6. |
PTM databases | |
| PhosphoSite | Q8WXG6. |
Proteomic databases | |
| PRIDE | Q8WXG6. |
Genome annotation databases | |
| Ensembl | ENST00000311027; ENSP00000310933; ENSG00000110514; Homo sapiens. [Genome view] |
| GeneID | 8567. |
| KEGG | hsa:8567. |
| UCSC | uc001neq.1. human. uc001ner.1. human. uc001nes.1. human. uc001net.1. human. uc001neu.1. human. uc001nev.1. human. uc001nex.1. human. |
Organism-specific databases | |
| CTD | 8567. |
| GeneCards | GC11P047247. |
| HGNC | HGNC:6766. MADD. |
| MIM | 603584. gene+phenotype. |
| PharmGKB | PA30523. |
| HUGE | Search... |
| GenAtlas | Search... |
Phylogenomic databases | |
| HOVERGEN | Q8WXG6. |
| OMA | GFQMHTR |
| OrthoDB | EOG9VX4QG |
Enzyme and pathway databases | |
| Pathway_Interaction_DB | tnfpathway. TNF receptor signaling pathway. |
Gene expression databases | |
| ArrayExpress | Q8WXG6. |
| Bgee | Q8WXG6. |
| Genevestigator | Q8WXG6. |
Family and domain databases | |
| InterPro | IPR005112. dDENN. IPR001194. DENN. IPR005113. uDENN. [Graphical view] |
| Pfam | PF03455. dDENN. 1 hit. PF02141. DENN. 1 hit. PF03456. uDENN. 1 hit. [Graphical view] |
| SMART | SM00801. dDENN. 1 hit. SM00799. DENN. 1 hit. SM00800. uDENN. 1 hit. [Graphical view] |
| PROSITE | PS50947. DDENN. 1 hit. PS50017. DEATH_DOMAIN. False negative. PS50211. DENN. 1 hit. PS50946. UDENN. 1 hit. [Graphical view] |
| ProtoNet | Search... |
Other Resources | |
| NextBio | 32121. |
| SOURCE | Search... |
Entry information
| Entry name | MADD_HUMAN | ||||||||
| Accession | Primary (citable) accession number: Q8WXG6 Secondary accession number(s): O15065 Q8WZ63 | ||||||||
| Entry history |
| ||||||||
| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation project | HPI (Human Proteome Initiative) | ||||||||
| Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. | ||||||||
Relevant documents
| Human chromosome 11 Human chromosome 11: entries, gene names and cross-references to MIM |
| Human entries with polymorphisms or disease mutations List of human entries with polymorphisms or disease mutations |
| Human polymorphisms and disease mutations Index of human polymorphisms and disease mutations |
| MIM cross-references Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot |
| SIMILARITY comments Index of protein domains and families |

Clusters with


