Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome

Cockrell, Lisa M.; Puckett, Mary; Goldman, Erinn H.; Khuri, Fadlo R.; Fu, Haian

doi:10.1038/onc.2009.382

Cited by 39 publications

(26 citation statements)

References 36 publications

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“…Reversible phosphorylation of ASK1 at Ser967 serves as a sensing mechanism, integrating diverse environmental cues to illicit critical biological responses through ASK1 (3,6). Stress signals often induce dephosphorylation of Ser967 and promote cell death and, indeed, Ser967 was dephosphorylated upon serum withdrawal (Fig.…”

Section: Diverse Growth Factor-initiated Pathways Impinge On Ask1 Atmentioning

confidence: 99%

“…Similarly, the protein phosphatase calcineurin activates ASK1 through the dephosphorylation of Ser967 (5). Conversely, increased ASK1/14-3-3 binding is correlated with decreasing ASK1 activity and increased cell survival (6,7). By controlling the phosphorylation status of Ser967, an upstream protein kinase cascade(s) may be able to integrate diverse signaling pathways with ASK1-mediated stress responses.…”

mentioning

confidence: 99%

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Integration of Apoptosis Signal-Regulating Kinase 1-Mediated Stress Signaling with the Akt/Protein Kinase B-IκB Kinase Cascade

Puckett

Goldman²,

Cockrell³

et al. 2013

Molecular and Cellular Biology

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g Cellular processes are tightly controlled through well-coordinated signaling networks that respond to conflicting cues, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress signals, and survival factors to ensure proper cell function. We report here a direct interaction between inhibitor of B kinase (IKK) and apoptosis signal-regulating kinase 1 (ASK1), unveiling a critical node at the junction of survival, inflammation, and stress signaling networks. IKK can be activated by growth factor stimulation or tumor necrosis factor alpha engagement. IKK forms a complex with and phosphorylates ASK1 at a sensor site, Ser967, leading to the recruitment of 14-3-3, counteracts stress signal-triggered ASK1 activation, and suppresses ASK1-mediated functions. An inhibitory role of IKK in JNK signaling has been previously reported to depend on NF-B-mediated gene expression. Our data suggest that IKK has a dual role: a transcription-dependent and a transcription-independent action in controlling the ASK1-JNK axis, coupling IKK to ROS and ER stress response. Direct phosphorylation of ASK1 by IKK also defines a novel IKK phosphorylation motif. Because of the intimate involvement of ASK1 in diverse diseases, the IKK/ASK1 interface offers a promising target for therapeutic development.

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Section: Diverse Growth Factor-initiated Pathways Impinge On Ask1 Atmentioning

confidence: 99%

mentioning

confidence: 99%

Integration of Apoptosis Signal-Regulating Kinase 1-Mediated Stress Signaling with the Akt/Protein Kinase B-IκB Kinase Cascade

Puckett

Goldman²,

Cockrell³

et al. 2013

Molecular and Cellular Biology

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“…In this complex, ASK1 activity is inhibited when ASK1 is bound to TRX, a small dithiol oxidoreductase involved in several processes across all species, from Archaeabacteria to mammals , through its N‐terminal thioredoxin‐binding domain (ASK1‐TBD) . Furthermore, the ASK1 signalosome also contains the 14‐3‐3 protein, which recognizes a phosphorylated motif located C‐terminally to the kinase domain (Fig. A).…”

Section: Introductionmentioning

confidence: 99%

The redox‐active site of thioredoxin is directly involved in apoptosis signal‐regulating kinase 1 binding that is modulated by oxidative stress

et al. 2019

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Keywords apoptosis signal-regulating kinase 1; mitogen-activated protein kinase kinase kinase; oxidative stress; protein-protein interaction; thioredoxin CorrespondenceAbbreviations ADH, adipic acid dihydrazide; ASK1, apoptosis signal-regulating kinase 1; DSBU, disuccinimidyl dibutyric urea; HSQC, heteronuclear single quantum correlation; MAP3K, mitogen-activated protein kinase kinase kinase; NMR, nuclear magnetic resonance; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect spectroscopy; SAXS, small-angle X-ray scattering; TBD, thioredoxin-binding domain; TROSY, transverse relaxation optimized spectroscopy; TRX, thioredoxin; XL-MS, chemical cross-linking coupled to mass spectrometry.

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“…The N-terminal region of ASK1 also has been implicated in binding CIB1 to detect Ca 2+ -based stress signaling, and in binding Fbxo21 to trigger innate antiviral signaling, among other proteinprotein interactions (24)(25)(26). The region C terminal to the kinase is less well studied, but contains a 14-3-3 protein-binding site housed within a predicted disordered sequence (27,28), followed by a region proposed to promote constitutive oligomerization of ASK1 (26). This C-terminal oligomerization region of ASK1 also has the capacity to directly bind to HIV Vif-1 and promote the innate antiviral response by APOBEC3G (8).…”

mentioning

confidence: 99%

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

Weijman

Kumar

Jamieson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Apoptosis signal-regulating kinases (ASK1-3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a molecular understanding of how ASK proteins are controlled remains obscure. Here, we report a biochemical analysis of the ASK1 kinase domain in conjunction with its N-terminal thioredoxin-binding domain, along with a central regulatory region that links the two. We show that in solution the central regulatory region mediates a compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation. The crystal structure of the central regulatory region reveals an unusually compact tetratricopeptide repeat (TPR) region capped by a cryptic pleckstrin homology domain. Biochemical assays show that both a conserved surface on the pleckstrin homology domain and an intact TPR region are required for ASK1 activity. We propose a model in which the central regulatory region promotes ASK1 activity via its pleckstrin homology domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. Such an architecture provides a mechanism for control of ASK-type kinases by diverse activators and inhibitors and demonstrates an unexpected level of autoregulatory scaffolding in mammalian stress-activated MAP kinase signaling.itogen-activated protein (MAP) kinase cascades transmit signals from membrane-associated receptors to intracellular targets to effect changes in cellular behavior. They form a hierarchical system in which activated upstream kinases (MAP3Ks) phosphorylate intermediate MAP kinase kinases (MAP2Ks), which in turn phosphorylate terminal MAP kinases, primarily ERK, p38, and JNK and their isoforms (1). Extensive studies have focused on the activation of RAS-RAF-MEK upstream in the ERK pathway and provided fertile ground for the discovery of new therapeutics (2). In contrast to the ERK pathway, which primarily promotes cellular proliferation, JNK and p38 phosphorylate a range of substrates to promote inflammation and cell death (1, 3). In addition, cross-regulation among the p38, JNK, and ERK pathways is important for the efficacy of various cancer therapies that are in use or in development (4, 5). Molecular details on the more diverse upstream regulation of the p38 and JNK pathways are currently less clear, however.Apoptosis signal-regulating kinases (ASK1-3) are MAP3Ks that trigger cellular responses to redox stress and inflammatory cytokines (6, 7) and play vital roles in innate immunity and viral infection (8-11). When activated, ASK1-3 activate JNK and p38 via phosphorylation of MAP2Ks (MKK3/4/6/7) (12). The key initiator role of ASK1-3 in this pathway means that either too much or too little ASK activity can have pathological effects. For instance, inhibiting ASK1 is beneficial against gastric cancer (13,14), but inactivating mutations in ASK1...

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Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome

Cited by 39 publications

References 36 publications

Integration of Apoptosis Signal-Regulating Kinase 1-Mediated Stress Signaling with the Akt/Protein Kinase B-IκB Kinase Cascade

Integration of Apoptosis Signal-Regulating Kinase 1-Mediated Stress Signaling with the Akt/Protein Kinase B-IκB Kinase Cascade

The redox‐active site of thioredoxin is directly involved in apoptosis signal‐regulating kinase 1 binding that is modulated by oxidative stress

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

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