Each family of MAPKs is composed of a set of three sequentially acting kinases: a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK). p38 (also known as CSBP, mHOG1, RK, and SAPK2) is the archetypal member of the second MAPK-related pathway in mammalian cells. The p38 module consists of several MAPKKKs, including MEKKs 1-4, MLK2 and -3, DLK, ASK1, Tpl2 (a.k.a. Cot), and Tak1, the MAPKKs MEK3 and MEK6 (a.k.a. MKK3 and MKK6, resp.), and the four known p38 isoforms (α, β, γ, and δ).
Being a member of the mitogen-activated protein (MAP) kinase kinase family, the Apoptosis Signal-regulating Kinase 1 (ASK1; EC activates downstream MAP kinases (MAPKs), c-Jun N-terminal kinases (JNKs) and p38 MAPKs, in response to various stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, lipopolysaccharide, and calcium overload. Activation of these pathways induces cellular responses such as apoptosis, differentiation, cell survival, and production of inflammatory cytokines.  Evidence is growing that ASK proteins play pivotal roles in the pathogenesis and pathology of a wide range of diseases in whichROSand/or ER stress may be common pathogenic factors, such as cardiovascular, neurodegenerative diseases, and cancers. At the molecular level, the activation of ASK1 is tightly regulated by phosphorylation of a threonine residue (Thr838 in human ASK1) within the activation loop of the kinase domain, which appears to be a common activation mechanism among the ASK family of proteins, i.e., ASK1, ASK2, NSY-1, and DASK1[1]. ASK1 forms a high molecular mass complex termed the ASK1 signalosome. Within the signalosome, ASK1 is homooligomerized through its C-terminal coiled-coil (CCC) domain, a process that is critical for ASK1 activation. Among the regulatory proteins that are involved in the activation of ASK1, such as TNF-α receptor-associated factor 2 (TRAF2), TRAF6, protein phosphatase 5 (PP5), and USP9X, the redox protein thioredoxin (Trx) plays a pivotal role: the reduced form of Trx binds to the N-terminal region of ASK1 and inhibits its kinase activity. Upon oxidation in response to ROS, Trx dissociates from ASK1, and ASK1 is then activated by the autophosphorylation of the Thr residue in its kinase domain[2].
AMP-activated protein kinase (AMPK; EC is a heterotrimeric enzyme with a key role in regulating cellular energy metabolism, cell growth and cell polarity. In response to a change in the intracellular AMP:ATP or ADP:ATP ratios it activates energy-producing pathways and inhibits energy-consuming processes. Activation of AMPK is triggered by phosphorylation of a threonine residue, which lies in the activation segment of the amino-terminal kinase domain of the α-subunit and results in a several-hundred-fold increase in activity. In mammals, calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ), LKB1, and transforming growth factor-β-activated kinase 1 (TAK1)  are the predominant kinases upstream of AMPK[3]. In turn, activated, phosphorylated AMPK can be inactivated by protein phosphatases (PP), e.g. PP2A, PP2Cα and Ppm1E.

[1] R. Hayakawa et al. Therapeutic targets in the ASK1-dependent stress signaling pathways. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2012, 88, 434–453.
[2] M. Soga, A. Matsuzawa, H. Ichijo. Oxidative Stress-Induced Diseases via the ASK1 Signaling Pathway. Int. J. Cell Biol. 2012, 2012,  439587.
[3] Structure of mammalian AMPK and its regulation byADP. B. Xiao. Nature 2011, 472, 230-233. 

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Axon ID Name Description From price
2179 ASK1 Inhibitor 10 Potent, selective, and orally bioavailable ASK1 inhibitor €130.00
3625 GNE-3511 Potent, selective, orally bioavailable and brain-penetrant DLK inhibitor €90.00
3895 GSK329 Highly potent and selective TNNI3K inhibitor €130.00
2366 NG 25 trihydrochloride Type II inhibitor of TAK1 (MAP3K7) and MAP4K2 (GCK) €75.00
1814 NQDI 1 Inhibitor of apoptosis signal-regulating kinase 1 (ASK1) €115.00
2956 Selonsertib Potent, highly selective, orally available, and ATP-competitive ASK1 inhibitor €90.00
3282 Takinib Potent and selective TAK1 (MAP3K7) inhibitor €105.00

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