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| Stress signaling: Stress granules RACK1 up MTK1
Stress granule formation inhibits apoptosis by suppressing stress-responsive MAPK pathways and sequestering the scaffold protein RACK1. A stressed cell may either activate cell cycle checkpoints, and repair and protective pathways, depending on the type of stress and the cellular context. The formation of cytoplasmic stress granules prevents mis-folded protein aggregation to enable cell survival, whereas the activation of p38 and c-Jun N-terminal protein kinases (JNKs) leads to apoptosis. Crosstalk between stress-induced pro-survival and pro-apoptotic pathways has not yet been described. In Nature Cell Biology, Arimoto et al. report that stress granules inhibit apoptosis by sequestering RACK1 and preventing p38 and JNK activation.
The MAPK kinase kinase MTK1 mediates apoptosis in response to stress by activating p38 and JNK. Mass spectrometry of proteins that co-immunoprecipitated with tagged MTK1 revealed an interaction with the signaling scaffold protein RACK1. Knockdown of RACK1 expression by short hairpin RNA inhibition (shRNAi) reduced MTK1 activation in response to cellular stress, whereas RACK1 overexpression led to moderate increases in MTK1 activation at lower RACK1 concentrations. Thus, RACK1 is necessary, but not sufficient, for MTK1 activation. The growth arrest and DNA damage-inducible (GADD45) family proteins bind to and activate MTK1 by relieving its autoinhibition, and allowing dimerization and autophosphorylation. Unlike GADD45, RACK1 was unable to relieve MTK1 autoinhibition, but it did promote MTK1 dimerization, suggesting that RACK1 acts as a bridge between two MTK1 molecules. Although RACK1 and GADD45 bind to the same region of MTK1, the binding of the two proteins appears to be independent. Taken together, these data suggest that RACK1 maintains MTK1 in an inactive but primed state in the absence of cellular stress. MTK1 was found to colocalize with RACK1 in unstressed cells. However, inducing stress granule formation led to the relocalization of RACK1 to the stress granules and a decrease in MTK1 association. Furthermore, cellular stresses that induced stress granule formation inhibited GADD45-mediated MTK1 activation and induction of apoptosis, suggesting that stresses that induce the pro-survival stress granule response also suppress pro-apoptotic pathway activation. Based on these findings, the authors propose a model in which RACK1 is sequestered to stress granules, preventing the activation of MTK1 by GADD45 and inhibiting apoptosis. Stresses that do not induce stress granule formation lead to GADD45-mediated MTK1 activation, p38/JNK phosphorylation and apoptosis. This suggests a potential mechanism for hypoxia-induced resistance to chemotherapy, as cells subjected to hypoxic shock form stress granules and are resistant to etoposide-induced apoptosis. Anna S. Kushnir
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