| IED ID | IndEnz0002002595 |
| Enzyme Type ID | protease002595 |
| Protein Name |
Mitogen-activated protein kinase kinase kinase 7 EC 2.7.11.25 Transforming growth factor-beta-activated kinase 1 TGF-beta-activated kinase 1 |
| Gene Name | Map3k7 Tak1 |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MSTASAASSSSSSSASEMIEAPSQVLNFEEIDYKEIEVEEVVGRGAFGVVCKAKWRAKDVAIKQIESESERKAFIVELRQLSRVNHPNIVKLYGACLNPVCLVMEYAEGGSLYNVLHGAEPLPYYTAAHAMSWCLQCSQGVAYLHSMQPKALIHRDLKPPNLLLVAGGTVLKICDFGTACDIQTHMTNNKGSAAWMAPEVFEGSNYSEKCDVFSWGIILWEVITRRKPFDEIGGPAFRIMWAVHNGTRPPLIKNLPKPIESLMTRCWSKDPSQRPSMEEIVKIMTHLMRYFPGADEPLQYPCQYSDEGQSNSATSTGSFMDIASTNTSNKSDTNMEQVPATNDTIKRLESKLLKNQAKQQSESGRLSLGASRGSSVESLPPTSEGKRMSADMSEIEARIVATAGNGQPRRRSIQDLTVTGTEPGQVSSRSSSPSVRMITTSGPTSEKPARSHPWTPDDSTDTNGSDNSIPMAYLTLDHQLQPLAPCPNSKESMAVFEQHCKMAQEYMKVQTEIALLLQRKQELVAELDQDEKDQQNTSRLVQEHKKLLDENKSLSTYYQQCKKQLEVIRSQQQKRQGTS |
| Enzyme Length | 579 |
| Uniprot Accession Number | Q62073 |
| Absorption | |
| Active Site | ACT_SITE 156; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-ProRule:PRU10027" |
| Activity Regulation | ACTIVITY REGULATION: Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation. {ECO:0000269|PubMed:29291351}. |
| Binding Site | BINDING 63; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25; Evidence={ECO:0000250|UniProtKB:O43318}; CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.25; Evidence={ECO:0000250|UniProtKB:O43318}; |
| DNA Binding | |
| EC Number | 2.7.11.25 |
| Enzyme Function | FUNCTION: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR) (PubMed:10748100, PubMed:16157589, PubMed:21183079, PubMed:29291351). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK (PubMed:16157589, PubMed:8533096, PubMed:29291351). MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis (PubMed:10748100). In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity (By similarity). Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (PubMed:28842570). {ECO:0000250|UniProtKB:O43318, ECO:0000269|PubMed:10748100, ECO:0000269|PubMed:16157589, ECO:0000269|PubMed:21183079, ECO:0000269|PubMed:28842570, ECO:0000269|PubMed:29291351, ECO:0000269|PubMed:8533096}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 42..50; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Binding site (1); Chain (1); Compositional bias (3); Cross-link (3); Domain (1); Modified residue (7); Mutagenesis (4); Nucleotide binding (1); Region (4) |
| Keywords | ATP-binding;Apoptosis;Cell membrane;Cytoplasm;Isopeptide bond;Kinase;Magnesium;Membrane;Metal-binding;Nucleotide-binding;Phosphoprotein;Reference proteome;Serine/threonine-protein kinase;Stress response;Transcription;Transcription regulation;Transferase;Ubl conjugation |
| Interact With | Q9WVI9-2; P70340; Q8CF89; Q99K90; P39429; Q9NYJ8; Q8N5C8; Q86Y07-1 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}; Cytoplasmic side {ECO:0000250}. Note=Although the majority of MAP3K7/TAK1 is found in the cytosol, when complexed with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2, it is also localized at the cell membrane. {ECO:0000250}. |
| Modified Residue | MOD_RES 184; /note="Phosphothreonine; by autocatalysis"; /evidence="ECO:0000250|UniProtKB:O43318"; MOD_RES 187; /note="Phosphothreonine; by autocatalysis"; /evidence="ECO:0000250|UniProtKB:O43318"; MOD_RES 192; /note="Phosphoserine; by autocatalysis"; /evidence="ECO:0000250|UniProtKB:O43318"; MOD_RES 367; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:O43318"; MOD_RES 389; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:19144319, ECO:0007744|PubMed:21183079"; MOD_RES 412; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:17242355, ECO:0007744|PubMed:19144319, ECO:0007744|PubMed:21183079"; MOD_RES 428; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:O43318" |
| Post Translational Modification | PTM: Association with TAB1/MAP3K7IP1 promotes autophosphorylation and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Thr-187 by PP2A and PPP6C leads to inactivation (By similarity). {ECO:0000250}.; PTM: 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation (PubMed:16157589). Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (PubMed:25632008). 'Lys-63'-linked polyubiquitination at Lys-158 by TRIM8 does not lead to proteasomal degradation but contributes to autophosphorylation and activation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:17548520, PubMed:29291351). {ECO:0000250|UniProtKB:O43318, ECO:0000269|PubMed:16157589, ECO:0000269|PubMed:17548520, ECO:0000269|PubMed:25632008, ECO:0000269|PubMed:29291351}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 10702308; 10725249; 10757786; 11356033; 12464436; 12466851; 12520002; 12545162; 12711537; 12805214; 12842894; 12904583; 14592977; 14610273; 15226265; 15647289; 15837794; 15894542; 15911626; 16141072; 16145668; 16186825; 16260493; 16301747; 16339560; 16360132; 16385569; 16446357; 16498455; 16556914; 16675448; 16754690; 16799562; 16831874; 16835226; 16857737; 16919269; 16940043; 17085580; 17114649; 17158449; 17197697; 17679097; 17855357; 17965022; 17967808; 18021073; 18079694; 18206350; 18299321; 18316610; 18573910; 18606667; 18606807; 18617512; 18762249; 18799693; 18805969; 18818394; 18829460; 18855897; 18984593; 19026643; 19116914; 19136967; 19196865; 19197243; 19201899; 19213760; 19224920; 19224984; 19234607; 19268530; 19419968; 19421137; 19536134; 19556242; 19675569; 19774455; 19793887; 19793892; 19820695; 19898473; 19927120; 19955178; 20014292; 20037141; 20037161; 20038579; 20062539; 20064449; 20065289; 20080763; 20164171; 20194509; 20213696; 20392264; 20478530; 20538596; 20551513; 20585657; 20696287; 20813258; 20855879; 20932476; 20959492; 21052097; 21267068; 21335610; 21367917; 21371434; 21383695; 21471444; 21472480; 21475303; 21606198; 21677750; 21771792; 21789165; 21822258; 21953618; 21979919; 21989986; 22016814; 22057290; 22069318; 22080947; 22143887; 22167179; 22219364; 22226633; 22307082; 22308391; 22326956; 22331902; 22337877; 22348103; 22365665; 22411628; 22467172; 22520462; 22590573; 22644295; 22649194; 22683931; 22698400; 22860133; 22941947; 22972987; 23148225; 23166301; 23226465; 23251462; 23322300; 23340735; 23391818; 23422957; 23460641; 23483698; 23505428; 23546880; 23776175; 23778976; 23790753; 23825189; 23892723; 23962979; 23972991; 23973329; 23982205; 23994637; 24036998; 24072697; 24077561; 24114841; 24120137; 24144697; 24194600; 24270572; 24277938; 24498425; 24534530; 24535827; 24633226; 24652804; 24751651; 24832470; 24833394; 24874739; 24952961; 24963009; 24980047; 24983318; 25050617; 25086610; 25146924; 25278099; 25418008; 25452303; 25521315; 25523394; 25535389; 25729924; 25828701; 25891214; 26092120; 26102028; 26132627; 26189595; 26269654; 26322481; 26347470; 26353931; 26371508; 26381601; 26444420; 26474655; 26564789; 26634297; 26648529; 26882989; 26973245; 26985063; 27026702; 27043411; 27121163; 27230958; 27245349; 27246297; 27249171; 27293199; 27402796; 27473013; 27601471; 27626380; 27685625; 27695001; 27696624; 27768832; 27995356; 28013046; 28045080; 28182011; 28220341; 28410990; 28530714; 28875549; 28898696; 28974699; 29024853; 29027124; 29107558; 29147012; 29163172; 29196442; 29228365; 29229953; 29247325; 29281682; 29292386; 29411501; 29415881; 29475001; 29500178; 29504713; 29558367; 29661023; 29667914; 29703898; 29796309; 29855498; 29894692; 30146158; 30361383; 30451876; 30582764; 30622220; 30639056; 30683914; 30765691; 30975711; 30988397; 31127032; 31241461; 31243089; 31301769; 31311865; 31387937; 31393024; 31402917; 31461199; 31545406; 31668971; 31813254; 31847895; 31869420; 31982140; 32071228; 32078472; 32108376; 32273474; 32349637; 32378287; 32382778; 32451485; 32460580; 32798288; 32865519; 32869445; 32979244; 33133065; 33139544; 33414375; 33436499; 33522247; 33549727; 34052945; |
| Motif | |
| Gene Encoded By | |
| Mass | 64,228 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:17989; RHEA:46608 |
| Cross Reference Brenda | 2.7.11.25; |