MAPKAPK5 is a serine/threonine kinase with dual roles as a tumor suppressor and developmental regulator. Primary function: MAPKAPK5 phosphorylates multiple substrates including p53, FOXO3, RHEB, and HSP27, modulating stress responses and cell cycle control [UniProt]. Mechanism: The protein acts as a negative regulator of mTORC1 signaling through RHEB phosphorylation and mediates Ras-induced senescence via p53 activation [UniProt]. MAPKAPK5 also participates in post-transcriptional MYC regulation by promoting FOXO3 nuclear localization, enabling miR-34b/c expression that represses MYC translation [UniProt]. Disease relevance: Biallelic loss-of-function variants in MAPKAPK5 cause neurocardiofaciodigital syndrome, characterized by severe developmental delay, intellectual disability, facial dysmorphism, cerebellar hypoplasia, and hypomyelination 12. Notably, the lncRNA MAPKAPK5-AS1 (antisense to this locus) shows oncogenic properties distinct from the protein kinase, promoting hepatocellular carcinoma and colorectal cancer progression through ceRNA mechanisms 3456. Clinical significance: MAPKAPK5 dysfunction represents an ultra-rare genetic cause of syndromic neurodevelopmental disease, while MAPKAPK5-AS1 dysregulation contributes to cancer pathogenesis, suggesting distinct therapeutic implications for protein versus RNA targets.