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) (O35099)
Organism: Mus musculus (Mouse)
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:0000250|UniProtKB:Q99683}. Endoplasmic reticulum {ECO:0000250}. Note=Interaction with 14-3-3 proteins alters the distribution of MAP3K5/ASK1 and restricts it to the perinuclear endoplasmic reticulum region. {ECO:0000250}.
Sequence: MGTEAGEGITFSVPPFASVGFCTIPEGGSCRRGGGAATAAEGEPSLQPLLVPPPPPPPGSFWNVESAAAPGTSCPTTAPGSSATRGRGNSGSGGGRRTTVAYVINEASQGQLVVAESEALQSLREACEAVGATLETLHFGKLDFGETAVLDRFYNADIAVVEMSDAFRQPSLFYHLGVRESFSMANNIILYCDTNSDSLQSLKEIICQKNTVCTGNYTFIPYMVTPHNKVYCCDSSFMKGLTELMQPNFELLLGPICLPLVDRFVQLLKVAQASSSQYFRESILSDIRKARNLYTGKELAAELARIRQRVDNIEVLTADIVINLLLSYRDIQDYDSIVKLVETLEKLPTFDLASHHHVKFHYAFALNRRNLPGDRAKALDIMIPMVQSEEQVASDMYCLVGRIYKDMFLDSNFTDTESRDHGASWFKKAFESEPTLQSGINYAVLLLAAGHQFESSFELRKVGVKLSSLLGKKGNLEKLQSYWEVGFFLGASVLANDHLRVIQASEKLFRLKTPAWYLKSIVETILIYKHFVKLTTEQPSAKQELVDFWMDFLVEATKTDVTVVRFPVLILEPTKIYQPSYLSINNEVEEKTISIWHVLPDDKKGIHEWNFGASSVRGVSISKFEERCCFLYVLHNSDDFQIYFCTELHCKRFFEMVNTITEEKGRGAEDGDCEGDSLEYDYEYDENGDRVVLGKGTYGIVYAGRDLSNQVRIAIKEIPERDSRYSQPLHEEIALHKHLKHKNIVQYLGSFSENGFIKIFMEQVPGGSLSALLRSKWGPLKDNEQTIGFYTKQILEGLKYLHDNQIVHRDIKGDNVLINTYSGVLKISDFGTSKRLAGINPCTETFTGTLQYMAPEIIDKGPRGYGKAADIWSLGCTIIEMATGKPPFYELGEPQAAMFKVGMFKVHPEIPESMSAEAKAFILKCFEPDPDKRACANDLLIDEFLKVSSKKKKTQPKLSALSTGSNEYLRSISLPVPVLVEDTSSSSEYGSVSPDTELKADPFSFKARAKSCGEKDGKGIRTLFLGIPDENFEDHSAPPSPEEKDSGFFMLRKDSERRATLHRILTEDQDKVVRNLMESLAQGAEEPKLKWEHITTLISSLREFVRSTDRKIIATTLSKLKLELDFDSHGISQVQVVLFGFQDAVNKVLRNHNIKPHWMFALDSIIRKAVQTAITILVPELRPHFSLASESDTADPEDLDVEDEHEELSSNQTVRRPQAITEDAVATSGVSTLSSTVSHDSQNAHRSLNVQLGRMKIETNRLLEELVRKERELQALLHQAIEEKDQEIRHLKLKSQPIDIPGFPVCHLNSPGTTTEDSELPGWLRENGADEDTISRFLAEDYTLVDVLYYVTRDDLKCLRLRGGMLCTLWKAIIDFRNKC
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [692-973]
- IPR025136: MAP3K, TRAFs-binding domain (domain) [172-552]
- IPR046873: MAP3K, HisK-N-like globin domain (domain) [1049-1180]
- IPR013761: Sterile alpha motif/pointed domain superfamily (homologous_superfamily) [1317-1379]
- IPR008271: Serine/threonine-protein kinase, active site (active_site) [806-818]
- IPR017441: Protein kinase, ATP binding site (binding_site) [693-716]
- IPR043969: MAP3K, PH domain (domain) [563-660]
- IPR000719: Protein kinase domain (domain) [687-945]
- IPR046872: MAP3K, deoxyribohydrolase domain (domain) [122-157]
Interaction partners: - Thioredoxin
- TNF receptor-associated factor 2
- Death domain-associated protein 6
- Serine/threonine-protein kinase/endoribonuclease IRE1
- Dual specificity mitogen-activated protein kinase kinase 4
- RAC-alpha serine/threonine-protein kinase
- Disabled homolog 2-interacting protein
- Dual specificity mitogen-activated protein kinase kinase 6
- Parkinson disease protein 7 homolog
- Stress-activated protein kinase JNK
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:0042221 (response to chemical), GO:0008219 (cell death), 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:0009893 (positive regulation of metabolic process), GO:0065009 (regulation of molecular function), GO:0006950 (response to stress), GO:0007154 (cell communication), GO:0048522 (positive regulation of cellular process), GO:0010942 (positive regulation of cell death), GO:0012501 (programmed cell death), GO:0080134 (regulation of response to stress), GO:0009966 (regulation of signal transduction), GO:0060255 (regulation of macromolecule metabolic process), GO:0010035 (response to inorganic substance), 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:0035556 (intracellular signal transduction), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0009611 (response to wounding), GO:0006979 (response to oxidative stress), GO:0080135 (regulation of cellular response to stress), GO:1901700 (response to oxygen-containing compound), GO:0010033 (response to organic substance), GO:0042127 (regulation of cell population proliferation), 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:0002931 (response to ischemia), GO:0034599 (cellular response to oxidative stress), 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:0048660 (regulation of smooth muscle cell proliferation), 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:0062197 (cellular response to chemical stress), GO:0048661 (positive regulation of smooth muscle cell proliferation), GO:0034976 (response to endoplasmic reticulum stress), GO:0042060 (wound healing), GO:0006915 (apoptotic process), GO:0051247 (positive regulation of protein metabolic process), GO:0042542 (response to hydrogen peroxide), GO:0051338 (regulation of transferase activity), GO:0000302 (response to reactive oxygen species), GO:1902531 (regulation of intracellular signal transduction), GO:0051174 (regulation of phosphorus metabolic process), GO:0042981 (regulation of apoptotic process), GO:1904705 (regulation of vascular associated smooth muscle cell proliferation), GO:0051403 (stress-activated MAPK cascade), GO:0045937 (positive regulation of phosphate metabolic process), GO:0071345 (cellular response to cytokine stimulus), GO:0043549 (regulation of kinase activity), GO:0043410 (positive regulation of MAPK cascade), GO:0034614 (cellular response to reactive oxygen species), GO:1904019 (epithelial cell apoptotic process), 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:0019220 (regulation of phosphate metabolic process), GO:1904707 (positive regulation of vascular associated smooth muscle cell proliferation), GO:0034612 (response to tumor necrosis factor), GO:0070301 (cellular response to hydrogen peroxide), GO:0070304 (positive regulation of stress-activated protein kinase signaling cascade), GO:0001932 (regulation of protein phosphorylation), GO:0010660 (regulation of muscle cell apoptotic process), 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: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:0071900 (regulation of protein serine/threonine kinase activity), GO:0043507 (positive regulation of JUN kinase activity), GO:0010663 (positive regulation of striated muscle cell apoptotic process), GO:0010662 (regulation of striated muscle cell apoptotic process), GO:1900745 (positive regulation of p38MAPK cascade), GO:0045860 (positive regulation of protein kinase activity), GO:0010665 (regulation of cardiac muscle cell apoptotic process), GO:0010666 (positive regulation of cardiac muscle cell apoptotic process), GO:0043405 (regulation of MAP kinase activity), GO:0071902 (positive regulation of protein serine/threonine 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:0005622 (intracellular anatomical structure), GO:0005737 (cytoplasm)