Signal transduction by the JNK group of MAP kinases.

Cellular functions, such as signal transmission, are carried out by 'modules' made up of many species of interacting molecules Understanding how modules work has depended on combining phenomenological analysis with molecular studies General principles that govern the structure and behaviour of modules may be discovered with help from synthetic sciences such as engineering and computer science, from stronger interactions between experiment and theory in cell biology, and from an appreciation of evolutionary constraints

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From molecular to modular cell biology.

The molecular details of mammalian stress-activated signal transduction pathways have only begun to be dissected. This, despite the fact that the impact of these pathways on the pathology of chroni...

Mammalian Mitogen-Activated Protein Kinase Signal Transduction Pathways Activated by Stress and Inflammation

Plant salt tolerance

Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

/pdf/live-or-let-die-the-cell-s-response-to-p53-3v8en5zmb2.pdf

Live or let die: the cell's response to p53

A Family of Stress-Inducible GADD45-like Proteins Mediate Activation of the Stress-Responsive MTK1/MEKK4 MAPKKK

The role of mitogen-activated protein (MAP) kinase cascades in integrating distinct upstream signals was studied in yeast. Mutants that were not able to activate PBS2 MAP kinase kinase (MAPKK; Pbs2p) at high osmolarity were characterized. Pbs2p was activated by two independent signals that emanated from distinct cell-surface osmosensors. Pbs2p was activated by MAP kinase kinase kinases (MAPKKKs) Ssk2p and Ssk22p that are under the control of the SLN1-SSK1 two-component osmosensor. Alternatively, Pbs2p was activated by a mechanism that involves the binding of its amino terminal proline-rich motif to the Src homology 3 (SH3) domain of a putative transmembrane osmosensor Sho1p.

https://science.sciencemag.org/content/sci/269/5223/554.full.pdf

Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor.

Stress-induced MAPK-dependent apoptosis is inhibited by the formation of stress granules, which sequester and inactivate the MTK1 activator RACK1. When confronted with environmental stress, cells either activate defence mechanisms to survive, or initiate apoptosis, depending on the type of stress. Certain types of stress, such as hypoxia, heatshock and arsenite (type 1 stress), induce cells to assemble cytoplasmic stress granules (SGs), a major adaptive defence mechanism. SGs are multimolecular aggregates of stalled translation pre-initiation complexes that prevent the accumulation of mis-folded proteins1. Type 2 stress, which includes X-rays and genotoxic drugs, induce apoptosis through the stress-activated p38 and JNK MAPK (SAPK) pathways. A functional relationship between the SG and SAPK responses is unknown. Here, we report that SG formation negatively regulates the SAPK apoptotic response, and that the signalling scaffold protein RACK1 functions as a mediator between the two responses. RACK1 binds to the stress-responsive MTK1 MAPKKK and facilitates its activation by type 2 stress; however, under conditions of type 1 stress, RACK1 is sequestered into SGs. Thus, type 1 conditions suppress activation of the MTK1–SAPK pathway and apoptosis induced by type 2 stress. These findings may be relevant to the problem of hypoxia-induced resistance to cancer chemotherapy.

Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways

NF-κB downregulates tumor necrosis factor (TNF)-induced c-Jun N-terminal kinase (JNK) activation that promotes cell death, but the mechanism is not yet fully understood. By using murine embryonic fibroblasts (MEFs) that are deficient in TNF receptor-associated factor (TRAF) 2 and TRAF5 (DKO) or p65 NF-κB subunit (p65KO), we demonstrate here that TNF stimulation leads to accumulation of reactive oxygen species (ROS), which is essential for prolonged mitogen-activated protein kinase (MAPK) activation and cell death. Interestingly, dying cells show necrotic as well as apoptotic morphological changes as assessed by electron microscopy and flow cytometry, and necrotic, but not apoptotic, cell death is substantially inhibited by antioxidant. Importantly, TNF does not induce ROS accumulation or prolonged MAPK activation in wild-type MEFs, indicating that TRAF-mediated NF-κB activation normally suppresses the TNF-induced ROS accumulation that subsequently induces prolonged MAPK activation and necrotic cell death

/pdf/nf-kb-inhibits-tnf-induced-accumulation-of-ros-that-mediate-3asu7mfygj.pdf

NF‐κB inhibits TNF‐induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death

The stress-responsive p38 MAPK, when activated by genotoxic stresses such as UV radiation, enhances p53 activity by phosphorylation and leads to cell cycle arrest or apoptosis. Here we report that a member of the protein phosphatase type 2C family, Wip1, has a role in down-regulating p38-p53 signaling during the recovery phase of the damaged cells. Wip1 was originally identified as a gene whose expression is induced following γ or UV radiation in a p53-dependent manner. We found that Wip1 is also inducible by other environmental stresses, such as anisomycin, H2O2 and methyl methane sulfonate. UV-induction of Wip1 requires p38 activity in addition to the wild-type p53. Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue. Furthermore, Wip1 expression attenuates UV-induced p53 phosphorylation at Ser33 and Ser46, residues previously reported to be phosphorylated by p38. Wip1 expression also suppresses both p53-mediated transcription and apoptosis in response to UV radiation. These results suggest that p53-dependent expression of Wip1 mediates a negative feedback regulation of p38-p53 signaling and contributes to suppression of the UV-induced apoptosis.

Mutsuhiro Takekawa

Papers

A Family of Stress-Inducible GADD45-like Proteins Mediate Activation of the Stress-Responsive MTK1/MEKK4 MAPKKK

Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor.

Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways

NF‐κB inhibits TNF‐induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death

p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation.