| Summary: | Summary: The stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38 are important players in cell-fate decisions in response to environmental stress signals. Crosstalk signaling between JNK and p38 is emerging as an important regulatory mechanism in inflammatory and stress responses. However, it is unknown how this crosstalk affects signaling dynamics, cell-to-cell variation, and cellular responses at the single-cell level. We established a multiplexed live-cell imaging system based on kinase translocation reporters to simultaneously monitor JNK and p38 activities with high specificity and sensitivity at single-cell resolution. Various stresses activated JNK and p38 with various dynamics. In all cases, p38 suppressed JNK activity in a cross-inhibitory manner. We demonstrate that p38 antagonizes JNK through both transcriptional and post-translational mechanisms. This cross-inhibition generates cellular heterogeneity in JNK activity after stress exposure. Our data indicate that this heterogeneity in JNK activity plays a role in fractional killing in response to UV stress. : Miura et al. investigate the role of signaling crosstalk between JNK and p38 at single-cell resolution. Suppression of JNK by p38 generates cell-to-cell variation in JNK activity under various stress conditions. This heterogeneous JNK activity leads to fractional killing in response to a severe stress such as UV irradiation. Keywords: JNK, p38, DUSP1, cross-inhibition, fluorescence imaging, KTR, cell-to-cell variability, stress
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