RPS6KA3 encodes RSK2, a serine/threonine kinase that functions as a critical downstream effector of ERK1/2-MAPK signaling with roles in both transcription and translation 1. RSK2 phosphorylates multiple substrates including transcription factors (CREB1, NR4A1, ETV1), ribosomal components (RPS6, EIF4B), and signaling regulators (TSC2, BAD, DAPK1), thereby promoting cell proliferation, survival, and protein synthesis [UniProt references]. In mammary tissue, RSK2 negatively regulates ERK1/2 activity and maintains estrogen homeostasis by limiting estrogen receptor responsiveness 2. Mutations in RPS6KA3 cause Coffin-Lowry syndrome, an X-linked developmental disorder characterized by intellectual disability, growth retardation, and skeletal anomalies resulting from loss of kinase activity 1. Recent evidence indicates RSK2 functions as a tumor suppressor in hepatocellular carcinoma (HCC); its inactivation cooperates with AXIN1 or β-catenin alterations to promote hepatocarcinogenesis 3. RSK2 inhibition in HCC cells activates compensatory RAS/MAPK signaling, which can be therapeutically targeted with MEK inhibitors 3. RSK2 also phosphorylates and promotes degradation of UBE2O, suppressing HCC growth and radioresistance 4. These findings establish RSK2 as a pleiotropic regulator of cell fate with distinct roles in developmental versus oncogenic contexts.