MAP3K5: Human Mitogen Activated Protein 3 Kinase
PDB Code: 2CLQ
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAP3K5) which plays an essential role in stress and immune response. ASK1 is activated by various stimuli including liposaccharides (LPS), oxidative stress (ROS), ER stress, influx of calcium ions and various cytokines such as tumor necrosis factor and Fas ligands. Signalling through the TRAF6-ASK1-p38 pathway has been shown to be essential for inflammatory response upon LPS stimulation. This role has been convincingly demonstrated by ASK1 -/- mice which show no macroscopic or microscopic phenotype but are resistant to LPS induced septic shock.
Human ASK1 is a protein of 1374 amino acids with a central serine/threonine kinase domain. Over-expression of wild-type or constitutively active ASK1 results in activation of the kinases MKK3/MKK6 and MKK4/MKK7 and in induction of apoptosis. However, the downstream events of ASK1 are variable depending on the cell types and cellular context and may lead also to cell differentiation, neurite outgrowth and induction of cytokines. In its inactive form ASK1 forms a homo-oligomer through its C-terminal coiled-coil domain. An ubiquitously expressed reduction/oxidation (redox) protein thioredoxin binds to the N-terminal of ASK1 and inhibits its activity. Upon oxidative stress stimulation formation of an intramolecular disulfide bridge leads to dissociation of that complex and ASK1 subsequent activation. Apart from it role in apoptosis ASK1 is an essential regulator of TLR-4 (Toll like receptor) mediated innate immunity.
Furthermore, ASK1 plays also an important role in polyglutamine (polyQ) diseases known to be the cause of at least nine inherited neurodegenerative disorders, including Huntington’s disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and six spinocerebellar ataxias as well as SCA3/Machado-Joseph disease [MJD]). PolyQ fragments accumulate as aggregates in the cytoplasm and/or nucleus and induce stress leading to neuronal cell death. ASK1 is also a potential therapeutic target for malignant fibrous histiocytomas, an particularly malignant form of undifferentiated liposarcomas.
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