Adaptive response to l‐serine deficiency is mediated by p38 MAPK activation via 1‐deoxysphinganine in normal fibroblasts

Reduced availability of l‐serine limits cell proliferation and leads to an adaptation to l‐serine‐deficient environment, the underlying molecular mechanism of which remain largely unexplored. Genetic ablation of 3‐phosphoglycerate dehydrogenase (Phgdh), which catalyzes the first step of de novo l‐serine synthesis, led to diminished cell proliferation and the activation of p38 MAPK and stress‐activated protein kinase/Jun amino‐terminal kinase in mouse embryonic fibroblasts under l‐serine depletion. The resultant l‐serine deficiency induced cyclin‐dependent kinase inhibitor 1a (Cdkn1a; p21) expression, which was mediated by p38 MAPK. Survival of the Phgdh‐deficient mouse embryonic fibroblasts was markedly reduced by p38 MAPK inhibition under l‐serine depletion, whereas p38 MAPK could be activated by 1‐deoxysphinganine, an atypical alanine‐derived sphingoid base that was found to accumulate in l‐serine‐depleted mouse embryonic fibroblasts. These observations provide persuasive evidence that when the external l‐serine supply is limited, l‐serine synthesized de novo in proliferating cells serves as a metabolic gatekeeper to maintain cell survival and the functions necessary for executing cell cycle progression. DATABASE: Gene Expression Omnibus, accession number GSE55687.