Therapeutic targets in the ASK1-dependent stress signaling pathways

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family that 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 the JNK and p38 pathways induces stress responses such as cell death, differentiation, and the production of inflammatory cytokines. A series of studies using ASK1-deficient mice have indicated that ASK1 plays important roles in many stress-related diseases, including cardiovascular and neurodegenerative diseases, suggesting that small compounds that inhibit ASK1 activity could possibly be used for the amelioration of the development and/or progression of these diseases. In this review, we provide an overview of the pathophysiological roles of ASK1-dependent signaling pathways and discuss the mechanistic basis for how these could serve as potential therapeutic targets.

Figure 1.

Mammalian stress-activated MAPK cascades. ASK1 and ASK2 are among a number of MAP3Ks that activate three isoforms of JNK and four isoforms of p38 through activation of MKK4/MKK7 and MKK3/MKK6, respectively.

Figure 2.

Overview of the functions of ASK1. ASK1 is activated by various stimuli, such as oxidative stress, ER stress, calcium influx, DNA damage-inducing agents, and receptor-mediated signaling through TNF receptor (TNFR), AngII receptor type 1 (AT₁), and Toll-like receptors TLR4, 7, and 8. Intracellular signaling molecules, such as TNFR-associated factor (TRAF) family proteins, TRAF2 and TRAF6, and CaMKII, act as activators of ASK1. In addition to such ASK1-activating molecules, many stimuli that activate ASK1 use reactive oxygen species (ROS) as signaling intermediates. Thioredoxin (Trx) is a redox protein that changes its structure depending on the cellular redox state. Only the reduced form of Trx binds to the N-terminus of ASK1 and inhibits ASK1 activity. Upon ROS stimulation, Trx is converted to the oxidized form and is dissociated from ASK1, leading to ASK1 activation. Activated ASK1 in turn activates the downstream p38 and JNK pathways and induces various cellular responses, including cell death, inflammation, differentiation, and survival.

Figure 3.

Possible involvement of ASK1 in insulin resistance and pancreatic β cell apoptosis. a) The ASK1-JNK pathway is involved in insulin resistance. In liver cells, TNFα activates the ASK1-JNK pathway through ROS production, which induces serine phosphorylation of insulin receptor substrate-1 (IRS-1) and subsequent inhibition of tyrosine phosphorylation of IRS, thereby inducing insulin resistance. b) ASK1 is involved in TXNIP-dependent pancreatic β cell apoptosis. In pancreatic β cells, TXNIP is localised mainly in the nucleus. Upon oxidative stress, TXNIP translocates into the mitochondria, binds to Trx2, and dissociates Trx2 from ASK1, leading to ASK1-dependent apoptosis.