Protein: Mitogen-activated protein kinase kinase kinase 5 (EC 2.7.11.25) (Apoptosis signal-regulating kinase 1) (ASK-1) (MAPK/ERK kinase kinase 5) (MEK kinase 5) (MEKK 5) (Q99683)
Organism: Homo sapiens (Human)
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).
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.
Sequence: MSTEADEGITFSVPPFAPSGFCTIPEGGICRRGGAAAVGEGEEHQLPPPPPGSFWNVESAAAPGIGCPAATSSSSATRGRGSSVGGGSRRTTVAYVINEASQGQLVVAESEALQSLREACETVGATLETLHFGKLDFGETTVLDRFYNADIAVVEMSDAFRQPSLFYHLGVRESFSMANNIILYCDTNSDSLQSLKEIICQKNTMCTGNYTFVPYMITPHNKVYCCDSSFMKGLTELMQPNFELLLGPICLPLVDRFIQLLKVAQASSSQYFRESILNDIRKARNLYTGKELAAELARIRQRVDNIEVLTADIVINLLLSYRDIQDYDSIVKLVETLEKLPTFDLASHHHVKFHYAFALNRRNLPGDRAKALDIMIPMVQSEGQVASDMYCLVGRIYKDMFLDSNFTDTESRDHGASWFKKAFESEPTLQSGINYAVLLLAAGHQFESSFELRKVGVKLSSLLGKKGNLEKLQSYWEVGFFLGASVLANDHMRVIQASEKLFKLKTPAWYLKSIVETILIYKHFVKLTTEQPVAKQELVDFWMDFLVEATKTDVTVVRFPVLILEPTKIYQPSYLSINNEVEEKTISIWHVLPDDKKGIHEWNFSASSVRGVSISKFEERCCFLYVLHNSDDFQIYFCTELHCKKFFEMVNTITEEKGRSTEEGDCESDLLEYDYEYDENGDRVVLGKGTYGIVYAGRDLSNQVRIAIKEIPERDSRYSQPLHEEIALHKHLKHKNIVQYLGSFSENGFIKIFMEQVPGGSLSALLRSKWGPLKDNEQTIGFYTKQILEGLKYLHDNQIVHRDIKGDNVLINTYSGVLKISDFGTSKRLAGINPCTETFTGTLQYMAPEIIDKGPRGYGKAADIWSLGCTIIEMATGKPPFYELGEPQAAMFKVGMFKVHPEIPESMSAEAKAFILKCFEPDPDKRACANDLLVDEFLKVSSKKKKTQPKLSALSAGSNEYLRSISLPVPVLVEDTSSSSEYGSVSPDTELKVDPFSFKTRAKSCGERDVKGIRTLFLGIPDENFEDHSAPPSPEEKDSGFFMLRKDSERRATLHRILTEDQDKIVRNLMESLAQGAEEPKLKWEHITTLIASLREFVRSTDRKIIATTLSKLKLELDFDSHGISQVQVVLFGFQDAVNKVLRNHNIKPHWMFALDSIIRKAVQTAITILVPELRPHFSLASESDTADQEDLDVEDDHEEQPSNQTVRRPQAVIEDAVATSGVSTLSSTVSHDSQSAHRSLNVQLGRMKIETNRLLEELVRKEKELQALLHRAIEEKDQEIKHLKLKSQPIEIPELPVFHLNSSGTNTEDSELTDWLRVNGADEDTISRFLAEDYTLLDVLYYVTRDDLKCLRLRGGMLCTLWKAIIDFRNKQT
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [685-939]
- IPR025136: MAP3K, TRAFs-binding domain (domain) [165-545]
- IPR046873: MAP3K, HisK-N-like globin domain (domain) [1042-1173]
- IPR013761: Sterile alpha motif/pointed domain superfamily (homologous_superfamily) [1310-1372]
- IPR008271: Serine/threonine-protein kinase, active site (active_site) [799-811]
- IPR017441: Protein kinase, ATP binding site (binding_site) [686-709]
- IPR043969: MAP3K, PH domain (domain) [556-653]
- IPR000719: Protein kinase domain (domain) [680-938]
- IPR046872: MAP3K, deoxyribohydrolase domain (domain) [115-150]
Interaction partners: - TNF receptor-associated factor 2
- Death domain-associated protein 6
- Serine/threonine-protein kinase/endoribonuclease IRE1
- Thioredoxin
- Dual specificity mitogen-activated protein kinase kinase 4
- Disabled homolog 2-interacting protein
- Dual specificity mitogen-activated protein kinase kinase 6
- Parkinson disease protein 7
- Dual specificity mitogen-activated protein kinase kinase 3
- Beta-arrestin-2
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0004672 (protein kinase activity), GO:0016772 (transferase activity, transferring phosphorus-containing groups), GO:0016773 (phosphotransferase activity, alcohol group as acceptor), GO:0004674 (protein serine/threonine kinase activity), GO:0016301 (kinase activity), GO:0004709 (MAP kinase kinase kinase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0023052 (signaling), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0042221 (response to chemical), GO:0006807 (nitrogen compound metabolic process), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0007165 (signal transduction), GO:0023056 (positive regulation of signaling), GO:0048584 (positive regulation of response to stimulus), GO:0019222 (regulation of metabolic process), GO:0071704 (organic substance metabolic process), GO:0044237 (cellular metabolic process), GO:0009893 (positive regulation of metabolic process), GO:0065009 (regulation of molecular function), GO:0006950 (response to stress), GO:0007154 (cell communication), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0010942 (positive regulation of cell death), GO:0080134 (regulation of response to stress), GO:0009966 (regulation of signal transduction), GO:0060255 (regulation of macromolecule metabolic process), GO:0006793 (phosphorus metabolic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0008284 (positive regulation of cell population proliferation), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0009967 (positive regulation of signal transduction), GO:0050790 (regulation of catalytic activity), GO:0044093 (positive regulation of molecular function), GO:1901564 (organonitrogen compound metabolic process), GO:0035556 (intracellular signal transduction), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0019538 (protein metabolic process), GO:0080135 (regulation of cellular response to stress), GO:1901700 (response to oxygen-containing compound), GO:0043170 (macromolecule metabolic process), GO:0010033 (response to organic substance), GO:0010941 (regulation of cell death), GO:0010646 (regulation of cell communication), GO:0031325 (positive regulation of cellular metabolic process), GO:0070887 (cellular response to chemical stimulus), GO:0033554 (cellular response to stress), GO:0010647 (positive regulation of cell communication), GO:0031323 (regulation of cellular metabolic process), GO:0080090 (regulation of primary metabolic process), GO:0097305 (response to alcohol), GO:0051246 (regulation of protein metabolic process), GO:0043067 (regulation of programmed cell death), GO:0000165 (MAPK cascade), GO:0070302 (regulation of stress-activated protein kinase signaling cascade), GO:0031098 (stress-activated protein kinase signaling cascade), GO:0043412 (macromolecule modification), GO:1902533 (positive regulation of intracellular signal transduction), GO:0043085 (positive regulation of catalytic activity), GO:1901701 (cellular response to oxygen-containing compound), GO:0034097 (response to cytokine), GO:0010562 (positive regulation of phosphorus metabolic process), GO:0071310 (cellular response to organic substance), GO:0043068 (positive regulation of programmed cell death), GO:2001235 (positive regulation of apoptotic signaling pathway), GO:0006796 (phosphate-containing compound metabolic process), GO:2001233 (regulation of apoptotic signaling pathway), GO:0036211 (protein modification process), GO:0051247 (positive regulation of protein metabolic process), GO:0051338 (regulation of transferase activity), GO:1902531 (regulation of intracellular signal transduction), GO:0051174 (regulation of phosphorus metabolic process), GO:0042981 (regulation of apoptotic process), GO:0051403 (stress-activated MAPK cascade), GO:0045937 (positive regulation of phosphate metabolic process), GO:0018193 (peptidyl-amino acid modification), GO:0071345 (cellular response to cytokine stimulus), GO:0016310 (phosphorylation), GO:0043549 (regulation of kinase activity), GO:0043410 (positive regulation of MAPK cascade), GO:0043410 (positive regulation of MAPK cascade), GO:0031401 (positive regulation of protein modification process), GO:0032872 (regulation of stress-activated MAPK cascade), GO:0043408 (regulation of MAPK cascade), GO:0043065 (positive regulation of apoptotic process), GO:0051347 (positive regulation of transferase activity), GO:0031399 (regulation of protein modification process), GO:0070555 (response to interleukin-1), GO:0006468 (protein phosphorylation), GO:0019220 (regulation of phosphate metabolic process), GO:0071396 (cellular response to lipid), GO:0034612 (response to tumor necrosis factor), GO:0070304 (positive regulation of stress-activated protein kinase signaling cascade), GO:0001932 (regulation of protein phosphorylation), GO:0045859 (regulation of protein kinase activity), GO:0042327 (positive regulation of phosphorylation), GO:0043406 (positive regulation of MAP kinase activity), GO:0001934 (positive regulation of protein phosphorylation), GO:0032874 (positive regulation of stress-activated MAPK cascade), GO:0042325 (regulation of phosphorylation), GO:0007254 (JNK cascade), GO:0046328 (regulation of JNK cascade), GO:0033674 (positive regulation of kinase activity), GO:0010661 (positive regulation of muscle cell apoptotic process), GO:0071356 (cellular response to tumor necrosis factor), GO:1900744 (regulation of p38MAPK cascade), GO:0046777 (protein autophosphorylation), GO:1900744 (regulation of p38MAPK cascade), GO:0071900 (regulation of protein serine/threonine kinase activity), GO:0043507 (positive regulation of JUN kinase activity), GO:0046330 (positive regulation of JNK cascade), GO:0045860 (positive regulation of protein kinase activity), GO:0071902 (positive regulation of protein serine/threonine kinase activity), GO:0043405 (regulation of MAP kinase activity), GO:0043506 (regulation of JUN kinase activity)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005829 (cytosol), GO:0098552 (side of membrane), GO:0005622 (intracellular anatomical structure), GO:0009986 (cell surface), GO:0005737 (cytoplasm), GO:0071944 (cell periphery), GO:0016020 (membrane), GO:0009897 (external side of plasma membrane), GO:0005886 (plasma membrane)