Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit

Ritt, Daniel A.; Abreu-Blanco, María Teresa; Bindu, Lakshman; Durrant, David; Zhou, Ming; Specht, Suzanne I.; Stephen, Andrew; Holderfield, Matthew; Morrison, Deborah K.

doi:10.1016/j.molcel.2016.10.029

Cited by 80 publications

(85 citation statements)

References 31 publications

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“…Recently, a small-molecule inhibitor, rigosertib, was shown to act as a RAS mimetic and interact with the RBDs of RAF kinases, RalGDS and PI3Ks, resulting in their inability to bind to activated RAS (Athuluri-Divakar et al, 2016). Recently, results from Ritt et al (2016) suggested a different mechanism on how rigosertib mediates its effects. The effects of rigosertib were seen to be largely indirect, mediated by the stress-induced phosphor-regulatory circuit that involves TNK cascade activation.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,382

1,350

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RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

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Section: Therapeutic Approachesmentioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,382

1,350

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“…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.…”

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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“…To further investigate whether signaling upstream of JNK1/2 is also influenced, we examined the activation of MAPK kinase (MEK), MKK3/6, MKK4, and MKK7, which activate downstream JNK1/2 . Notably, the HFD‐ or PA‐induced increase in phosphorylated MKK7, but not phosphorylated MEK, MKK3/6, or MKK4, was significantly inhibited by TPL2 deficiency, whereas TPL2 overexpression led to a further increase in MKK7 phosphorylation (Fig.…”

Section: Resultsmentioning

confidence: 99%