MAP3K5
entrez
4217
canonical
uniprot
Q99683
canonical
ensembl
ENSG00000197442
resolver
ensp
ENSP00000351908
resolver
ensp
ENSP00000514039
resolver
ensp
ENSP00000776936
resolver
enst
ENST00000698928
resolver
genesymbol
MAP3K5
resolver
genesymbol_syn
ASK1
resolver
genesymbol_syn
MAPKKK5
resolver
genesymbol_syn
MEKK5
resolver
hgnc
HGNC:6857
resolver
uniprot
A0A8V8TMH5
resolver
uniprot
A6NIA0
resolver
uniprot
B4DGB2
resolver
uniprot
Q5THN3
resolver
uniprot
Q99461
resolver
uniprot_entry
A0A8V8TMH5_HUMAN
resolver
uniprot_entry
M3K5_HUMAN
resolver
uniprot_sec
A6NIA0
resolver
uniprot_sec
B4DGB2
resolver
uniprot_sec
Q5THN3
resolver
uniprot_sec
Q99461
resolver
activity_regulation
ACTIVITY REGULATION: Activated 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 (PubMed:17210579, PubMed:9564042). 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 (PubMed:10688666, PubMed:11920685, PubMed:9774977). 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 (PubMed:11689443). Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 (PubMed:11154276, PubMed:15094778). Phosphorylation of Ser-966 induces association of MAP3K5/ASK1 with the 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity (PubMed:10411906, PubMed:14688258). Calcium/calmodulin-activated protein phosphatase calcineurin (PPP3CA) has been shown to directly dephosphorylate this site (PubMed:14749717). SOCS1 binds to ASK1 by recognizing phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells (PubMed:16407264). Also dephosphorylated and activated by PGAM5. Contains an N-terminal autoinhibitory domain. Once activated targeted for proteasomal degradation by RC3H2-mediated ubiquitination (PubMed:24448648). {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:14688258, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:16407264, ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:24448648, ECO:0000269|PubMed:26095851, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}.
uniprot
proteins
amino_acid_sequence
MSTEADEGITFSVPPFAPSGFCTIPEGGICRRGGAAAVGEGEEHQLPPPPPGSFWNVESAAAPGIGCPAATSSSSATRGRGSSVGGGSRRTTVAYVINEASQGQLVVAESEALQSLREACETVGATLETLHFGKLDFGETTVLDRFYNADIAVVEMSDAFRQPSLFYHLGVRESFSMANNIILYCDTNSDSLQSLKEIICQKNTMCTGNYTFVPYMITPHNKVYCCDSSFMKGLTELMQPNFELLLGPICLPLVDRFIQLLKVAQASSSQYFRESILNDIRKARNLYTGKELAAELARIRQRVDNIEVLTADIVINLLLSYRDIQDYDSIVKLVETLEKLPTFDLASHHHVKFHYAFALNRRNLPGDRAKALDIMIPMVQSEGQVASDMYCLVGRIYKDMFLDSNFTDTESRDHGASWFKKAFESEPTLQSGINYAVLLLAAGHQFESSFELRKVGVKLSSLLGKKGNLEKLQSYWEVGFFLGASVLANDHMRVIQASEKLFKLKTPAWYLKSIVETILIYKHFVKLTTEQPVAKQELVDFWMDFLVEATKTDVTVVRFPVLILEPTKIYQPSYLSINNEVEEKTISIWHVLPDDKKGIHEWNFSASSVRGVSISKFEERCCFLYVLHNSDDFQIYFCTELHCKKFFEMVNTITEEKGRSTEEGDCESDLLEYDYEYDENGDRVVLGKGTYGIVYAGRDLSNQVRIAIKEIPERDSRYSQPLHEEIALHKHLKHKNIVQYLGSFSENGFIKIFMEQVPGGSLSALLRSKWGPLKDNEQTIGFYTKQILEGLKYLHDNQIVHRDIKGDNVLINTYSGVLKISDFGTSKRLAGINPCTETFTGTLQYMAPEIIDKGPRGYGKAADIWSLGCTIIEMATGKPPFYELGEPQAAMFKVGMFKVHPEIPESMSAEAKAFILKCFEPDPDKRACANDLLVDEFLKVSSKKKKTQPKLSALSAGSNEYLRSISLPVPVLVEDTSSSSEYGSVSPDTELKVDPFSFKTRAKSCGERDVKGIRTLFLGIPDENFEDHSAPPSPEEKDSGFFMLRKDSERRATLHRILTEDQDKIVRNLMESLAQGAEEPKLKWEHITTLIASLREFVRSTDRKIIATTLSKLKLELDFDSHGISQVQVVLFGFQDAVNKVLRNHNIKPHWMFALDSIIRKAVQTAITILVPELRPHFSLASESDTADQEDLDVEDDHEEQPSNQTVRRPQAVIEDAVATSGVSTLSSTVSHDSQSAHRSLNVQLGRMKIETNRLLEELVRKEKELQALLHRAIEEKDQEIKHLKLKSQPIEIPELPVFHLNSSGTNTEDSELTDWLRVNGADEDTISRFLAEDYTLLDVLYYVTRDDLKCLRLRGGMLCTLWKAIIDFRNKQT
uniprot
proteins
ec_number
2.7.11.25
uniprot
proteins
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 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:14688258, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544, ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:17220297, ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:26095851, ECO:0000269|PubMed:8940179, ECO:0000269|PubMed:8974401, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}.
uniprot
proteins
mass_dalton
154537
uniprot
proteins
mutagenesis
MUTAGEN 32; /note="R->K: No effect on methylation by PRMT1."; /evidence="ECO:0000269|PubMed:22095282"; MUTAGEN 78; /note="R->K: Reduced methylation by PRMT1. Abolishes methylation by PRMT1 and PRMT1-mediated inhibition of MAPK35 activation; when associated with K-80."; /evidence="ECO:0000269|PubMed:22095282"; MUTAGEN 80; /note="R->K: Reduced methylation by PRMT1. Abolishes methylation by PRMT1 and PRMT1-mediated inhibition of MAPK35 activation; when associated with K-78."; /evidence="ECO:0000269|PubMed:22095282"; MUTAGEN 709; /note="K->M: Loss of kinase activity. Inhibits activation of JNK and apoptosis mediated by TNFRSF6 and DAXX. Does not affect interaction with TRIM48."; /evidence="ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:29186683, ECO:0000269|PubMed:9743501"; MUTAGEN 709; /note="K->R: Loss of kinase activity. Abolishes DAXX-mediated apoptosis. Loss of RC3H2-mediated ubiquitination."; /evidence="ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:24448648, ECO:0000269|PubMed:9743501"; MUTAGEN 838; /note="T->A: Does not affect interaction with TRIM48."; /evidence="ECO:0000269|PubMed:29186683"; MUTAGEN 966; /note="S->A: Enhanced induction of apoptosis, increased kinase activity, and loss of YWHAG binding."; /evidence="ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:15094778"; MUTAGEN 1033; /note="S->A: Enhanced induction of apoptosis and increased kinase activity."; /evidence="ECO:0000269|PubMed:15094778
uniprot
proteins
post_translational_modification
PTM: Phosphorylated 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. 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. Phosphorylation at Ser-966 in response to oxidative stress is negatively regulated by PPIA/CYPA (PubMed:26095851). {ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12556535, ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:16407264, ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:17937911, ECO:0000269|PubMed:18948261, ECO:0000269|PubMed:19590015, ECO:0000269|PubMed:19749799, ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:26095851}.; PTM: Ubiquitinated (PubMed:16038411, PubMed:17220297, PubMed:29186683). Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination, leading to proteasomal degradation (PubMed:17220297). Ubiquitinated by RC3H2 in a TRIM48-dependent manner (PubMed:29186683). {ECO:0000269|PubMed:16038411, ECO:0000269|PubMed:17220297, ECO:0000269|PubMed:29186683}.; PTM: Methylation at Arg-78 and Arg-80 by PRMT1 promotes association of MAP3K5 with thioredoxin and negatively regulates MAP3K5 association with TRAF2, inhibiting MAP3K5 activation (PubMed:22095282). Methylation is blocked by ubiquitination of PRMT1 by TRIM48 (PubMed:29186683). {ECO:0000269|PubMed:22095282, ECO:0000269|PubMed:29186683}.
uniprot
proteins
protein_family
MAP kinase kinase kinase subfamily
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
STE Ser/Thr protein kinase family
uniprot
proteins
pubmed
10411906
uniprot
proteins
pubmed
10688666
uniprot
proteins
pubmed
10849426
uniprot
proteins
pubmed
11029458
uniprot
proteins
pubmed
11090355
uniprot
proteins
pubmed
11154276
uniprot
proteins
pubmed
11298454
uniprot
proteins
pubmed
11427728
uniprot
proteins
pubmed
11689443
uniprot
proteins
pubmed
11920685
uniprot
proteins
pubmed
12556535
uniprot
proteins
pubmed
12697749
uniprot
proteins
pubmed
12813029
uniprot
proteins
pubmed
14574404
uniprot
proteins
pubmed
14688258
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
14749717
uniprot
proteins
pubmed
15023544
uniprot
proteins
pubmed
15094778
uniprot
proteins
pubmed
15310755
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15701637
uniprot
proteins
pubmed
16038411
uniprot
proteins
pubmed
16129676
uniprot
proteins
pubmed
16407264
uniprot
proteins
pubmed
17210579
uniprot
proteins
pubmed
17220297
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17389591
uniprot
proteins
pubmed
17456047
uniprot
proteins
pubmed
17724081
uniprot
proteins
pubmed
17883330
uniprot
proteins
pubmed
17937911
uniprot
proteins
pubmed
18088087
uniprot
proteins
pubmed
18408005
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18948261
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
19389260
uniprot
proteins
pubmed
19590015
uniprot
proteins
pubmed
19749799
uniprot
proteins
pubmed
20358250
uniprot
proteins
pubmed
22095282
uniprot
proteins
pubmed
23102700
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24448648
uniprot
proteins
pubmed
26095851
uniprot
proteins
pubmed
27825085
uniprot
proteins
pubmed
29186683
uniprot
proteins
pubmed
8940179
uniprot
proteins
pubmed
8974401
uniprot
proteins
pubmed
9564042
uniprot
proteins
pubmed
9743501
uniprot
proteins
pubmed
9774977
uniprot
proteins
sequence_length
1374
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:26095851}. Endoplasmic reticulum. Note=Interaction with 14-3-3 proteins alters the distribution of MAP3K5/ASK1 and restricts it to the perinuclear endoplasmic reticulum region.
uniprot
proteins