Roles of MAPKKK ASK1 in Stress-Induced Cell Death.

Abstract

ABSTRACT. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein (MAP) kinase kinase kinase that activates the c-Jun N-terminal kinase (JNK) and p38 MAP kinase signaling cascades. Recent findings from analyses of ASK1-deficient mice have revealed that ASK1 is required for apoptosis induced by oxidative stress, TNF and endoplasmic reticulum (ER) stress. In addition, several lines of evidence have suggested that ASK1 has diverse functions in the decision of cell fate beyond its pro-apoptotic activity. Thus, ASK1 appears to be a pivotal component not only in stress-induced cell death but also in a broad range of biological activities in order for cells to adapt to or oppose various stresses. Key words: MAPKKK/ASK1/JNK/p38/apoptosisThe mitogen-activated protein (MAP) kinase cascades are multifunctional signaling pathways that are evolutionally well conserved in all eukaryotic cells (Ichijo, 1999;Widmann, 1999;Kyriakis and Avruch, 2001). Three MAP kinase cascades that converge on ERKs, c-Jun N-terminal kinases (JNKs), and p38 MAP kinases have been extensively characterized, and each consists of three classes of serine/threonine kinases, MAP kinase, MAP kinase kinase (MAPKK, also referred to as MEK) and MAPKK kinase (MAPKKK). MAPKKK phosphorylates and thereby activates MAPKK, and activated MAPKK in turn phosphorylates and activates MAP kinase. Among the three MAP kinase cascades, two of them that converge on JNKs and p38 MAP kinases are preferentially activated by cytotoxic stresses such as UV radiation, X-ray, heat shock and osmotic shock, and by proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (Tibbles and Woodgett, 1999). One of the important biological responses mediated through these stress-activated MAP kinase pathways appears to be the decision of cell fate by regulating apoptosis. The possible roles of the JNK pathway in proapoptosis signaling have been demonstrated by knockout mouse studies. Mice lacking the JNK3 gene were reported to exhibit marked reduction in excitotoxicity-induced apoptosis of hippocampal neurons . JNK2 was shown to be required for apoptosis of immature thymocytes induced by anti-CD3 antibody but not for activationinduced cell death of mature T cells (Sabapathy et al., 1999). Compound mutant mice lacking the JNK1 and JNK2 genes suggested that JNK1 and JNK2 regulate region-specific apoptosis during early brain development (Kuan et al., 1999). Several lines of evidence have also suggested the pro-apoptotic roles of the p38 pathway (Xia et al., 1995;Kawasaki et al., 1997;Harper and LoGrasso et al., 2001), although they have not yet been supported by data of mice deficient for the p38 genes.Apoptosis signal-regulating kinase 1 (ASK1)/MAPKKK5 is a ubiquitously expressed MAPKKK that activates the JNK and p38 pathways by directly phosphorylating and thereby activating their respective MAPKKs, MKK4 (SEK1)/MKK7 and MKK3/MKK6 Ichijo et al., 1997) (Fig. 1). Overexpression of wild-type or constitutively active ASK1 induces apop...

Down-regulation of the Mixed-lineage Dual Leucine Zipper-bearing Kinase by Heat Shock Protein 70 and Its Co-chaperone CHIP

“…Park et al (55) have found that Hsp70 can inhibit JNK activation in cells exposed to UV irradiation and that this inhibitory function is linked to the Hsp70 ability to directly bind JNK and suppress its association with and phosphorylation by MKK4. The anti-apoptotic activity of Hsp70 is also reflected by its capacity to interact with apoptosis signal-regulating kinase 1, a mitogen-activated protein kinase kinase kinase of the JNK and p38 MAPK (mitogen-activated protein kinase) signaling pathways that is required for cytokine-and stress-induced apoptosis (56). In this case, Hsp70 binding prevents both oligomerization of apoptosis signal-regulating kinase 1 (ASK1), an event required for its activation, as well as ASK1-dependent apoptosis (57).…”

Emergent decision-making in biological signal transduction networks

“…In addition to those ligands, ''Stress'' is an input representing environmental stress factors such as UV light or reactive oxygen species (33,34), and there is a nonregulated calcium pump (external calcium pump). Calcium pumps are regulated mostly by calcium and hormonal factors that are not included in the current network (35).…”

“…These are (i) Akt, a major regulator of apoptotic systems (24), (ii) the mitogen-activated protein kinase (MAPK) Erk, a major regulator of cell division (34), and (iii) Rac and Cdc42, two important regulators of cytoskeletal systems (28). The MAPK's SAPK and p38 are also outputs of the network, but they respond to stress and TNF/IL-1 (33,34), as documented in SI Text. The experiments in the present work involve ''stress-limited'' inputs, meaning that stress and TNF/IL-1 are at low, background levels.…”

Critical Roles of Threonine 187 Phosphorylation in Cellular Stress-induced Rapid and Transient Activation of Transforming Growth Factor-β-activated Kinase 1 (TAK1) in a Signaling Complex Containing TAK1-binding Protein TAB1 and TAB2

“…The JNK and p38 pathways are activated by corresponding upstream MAP2Ks, such as MKK4/7 and MKK3/6, respectively (6 -10). In contrast to the simple combinations of MAPKs and MAP2Ks, more than 10 MAP3Ks that control the JNK and p38 pathways have been identified to date, and it has not been clear which MAP3K contributes mainly to the stress-induced MAPKs pathway (11)(12)(13)(14). On the other hand, the transcriptional activity of NF-B is regulated by IB kinase (IKK)-mediated degradation of IBs and subsequent nuclear translocation of the NF-B complex (15).…”