A

Phenotypic plasticity, the ability to change diverse traits without altering genomic information, is fundamental for organismal adaptations to changing environments. The mitogen-activated protein kinase (MAPK) pathway plays a key role in cellular adaptations to changing environments. To analyze the contributions of the MAPK p38 and its interaction partners to phenotypic plasticity in an animal, we established an in vivo proximity labeling proteomics method called ContinuumID. With this method, we built an atlas of PMK-1 physical interactors during development, in specific tissues, and during exposure to osmotic, ultraviolet, or oxidative stressors. We identified multiple stable and dynamic developmental stage-, tissue-, and stress-specific PMK-1 interactors. Phenotypic analyses of animals in which specific interactors were knocked down revealed considerable variability of diverse PMK-1-dependent outputs. These included target gene expression, survival under stress, lysosomal homeostasis during development, and neuronal integrity during aging. PMK-1 interactors exerted positive, negative, and neutral contributions to these outputs within and across functional pathways. Comparing developmental and stress-induced activation of PMK-1 and the regulatory functions of its interactors revealed that PMK-1 integrates the regulation of highly conserved protein synthesis and RNA processing pathways with that of rapidly changing signaling and metabolic adaptations to confer distinct survival advantages or disadvantages during stress.