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MGP001906

UniProt Annotations

Entry Information
Gene Namemitogen-activated protein kinase kinase kinase 5
Protein EntryM3K5_HUMAN
UniProt IDQ99683
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; IsoId=Q99683-1; Sequence=Displayed; Name=2; IsoId=Q99683-2; Sequence=VSP_056182; Note=No experimental confirmation available.;
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
CofactorName=Mg(2+); Xref=ChEBI:CHEBI:18420;
Enzyme RegulationActivated by various stressors, including oxidative stress, endoplasmic reticulum stress, and calcium overload, as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) and lipopolysaccharide (LPS). Homophilic association of MAP3K5/ASK1 through the C- terminal coiled-coil domains and the heteromeric complex formation of MAP3K5/ASK1 with the reduced form of thioredoxin (TXN), constitutes an inactive form of the kinase. Upon ROS-induced dissociation of TXN from MAP3K5/ASK1, TRAF2 and TRAF6 are reciprocally recruited to MAP3K5/ASK1 and form the active MAP3K5/ASK1 signalosome, in which TRAF2 and TRAF6 appear to facilitate the active configuration of MAP3K5/ASK1. MAP3K5/ASK1 activity is also regulated through several phosphorylation and dephosphorylation events. Thr-838 is an activating phosphorylation site that is autophosphorylated and phosphorylated by MAP3K6/ASK2 and dephosphorylated by PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 and AKT2. Phosphorylation of Ser-966 induces association of MAP3K5/ASK1 with the 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity. Calcium/calmodulin-activated protein phosphatase calcineurin (PPP3CA) has been shown to directly dephosphorylate this site. SOCS1 binds to ASK1 by recognizing phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Also dephosphorylated and activated by PGAM5. Contains an N-terminal autoinhibitory domain. {ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666, ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11689443, ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12556535, ECO:0000269|PubMed:12697749, ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:16407264, ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}.
FunctionSerine/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 signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). 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 MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). {ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666, ECO:0000269|PubMed:10849426, ECO:0000269|PubMed:11029458, ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11689443, ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12697749, ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544, ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:17220297, ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:8940179, ECO:0000269|PubMed:8974401, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}.
InductionBy TNF. Inhibited by HIV-1 Nef.
InteractionP31749:AKT1; NbExp=2; IntAct=EBI-476263, EBI-296087; P05067:APP; NbExp=2; IntAct=EBI-476263, EBI-77613; P49407:ARRB1; NbExp=3; IntAct=EBI-476263, EBI-743313; P32121:ARRB2; NbExp=2; IntAct=EBI-476263, EBI-714559; Q5VWQ8:DAB2IP; NbExp=2; IntAct=EBI-476263, EBI-2871881; Q9UER7:DAXX; NbExp=7; IntAct=EBI-476263, EBI-77321; P25445:FAS; NbExp=2; IntAct=EBI-476263, EBI-494743; P46734:MAP2K3; NbExp=2; IntAct=EBI-476263, EBI-602462; Q9WTR2:Map3k6 (xeno); NbExp=3; IntAct=EBI-476263, EBI-1254790; Q96EZ8:MCRS1; NbExp=3; IntAct=EBI-476263, EBI-348259; P63098:PPP3R1; NbExp=2; IntAct=EBI-476263, EBI-915984; Q16637:SMN2; NbExp=3; IntAct=EBI-476263, EBI-395421; P10599:TXN; NbExp=2; IntAct=EBI-476263, EBI-594644; P31946:YWHAB; NbExp=3; IntAct=EBI-476263, EBI-359815; P63104:YWHAZ; NbExp=3; IntAct=EBI-476263, EBI-347088; Q969S3:ZNF622; NbExp=14; IntAct=EBI-476263, EBI-2687480;
PtmPhosphorylated at Thr-838 through autophosphorylation and by MAP3K6/ASK2 which leads to activation. Thr-838 is dephosphorylated by PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 and AKT2. Phosphorylated at Ser-966 which induces association of MAP3K5/ASK1 with the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity. Calcineurin (CN) dephosphorylates this site. Also dephosphorylated and activated by PGAM5. {ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12556535, ECO:0000269|PubMed:12697749, ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:16407264, ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:17937911, ECO:0000269|PubMed:18088087, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:18948261, ECO:0000269|PubMed:19369195, ECO:0000269|PubMed:19590015, ECO:0000269|PubMed:19749799, ECO:0000269|PubMed:23102700}.
PtmUbiquitinated. Tumor necrosis factor (TNF) induces TNFR2- dependent ubiquitination leading to proteasomal degradation. {ECO:0000269|PubMed:16038411, ECO:0000269|PubMed:17220297}.
SimilarityBelongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationCytoplasm. Endoplasmic reticulum. Note=Interaction with 14-3-3 proteins alters the distribution of MAP3K5/ASK1 and restricts it to the perinuclear endoplasmic reticulum region.
SubunitHomodimer when inactive. Binds both upstream activators and downstream substrates in multimolecular complexes. Associates with and inhibited by HIV-1 Nef. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF. This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis. Interacts with SOCS1 which recognizes phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN. Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PGAM5, PIM1, PPP5C, SOCS1, STUB1, TRAF2, TRAF6 and TXN. Interacts with ERN1 in a TRAF2-dependent manner. Interacts with calcineurin subunit PPP3R1 and with PPM1L (By similarity). Interacts (via N-terminus) with RAF1 and this interaction inhibits the proapoptotic function of MAP3K5. Interacts with DAB2IP (via N-terminus C2 domain); the interaction occurs in a TNF-alpha-dependent manner. Interacts with DUSP13/DUSP13A; may positively regulate apoptosis. {ECO:0000250, ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666, ECO:0000269|PubMed:11090355, ECO:0000269|PubMed:11298454, ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11689443, ECO:0000269|PubMed:12556535, ECO:0000269|PubMed:12813029, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544, ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:15310755, ECO:0000269|PubMed:15701637, ECO:0000269|PubMed:16038411, ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:16407264, ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:17220297, ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:17456047, ECO:0000269|PubMed:17724081, ECO:0000269|PubMed:18408005, ECO:0000269|PubMed:19590015, ECO:0000269|PubMed:19749799, ECO:0000269|PubMed:20358250, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9743501, ECO:0000269|PubMed:9774977}.
Tissue SpecificityAbundantly expressed in heart and pancreas.
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