Spatiotemporal regulation of MKK4 dictates switch-like JNK activation and binary cell-fate decisions.

ABSTRACT: The JNK pathway converts graded (analogue) stress stimuli into a switch-like (digital) response, thereby dictating binary, all-or-none cell-fate decisions such as survival or death. However, the underlying mechanism remains unclear. Here, we report that the stress-induced modulation of MKK4 spatiotemporal dynamics serves as an analogue-to-digital converter for JNK signalling. Under steady-state conditions, MKK4 shuttles slowly between the nucleus and cytoplasm, but its shuttling rate increases markedly under stress via JNK-mediated feedback regulation. Experimental and mathematical analyses reveal that the increased shuttling rate, coupled with the predominant nuclear localisation of MKK4, cooperatively generates a switch-like JNK activation in response to graded stress stimuli. Disruption

SUBMITTER: Moriizumi H 

PROVIDER: S-EPMC12783738 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature