RPS6KA2 encodes RSK3, a serine/threonine kinase that functions downstream of ERK signaling in the MAPK pathway 1. The protein plays complex roles in cellular homeostasis, acting as both a tumor suppressor and oncogenic factor depending on cellular context. In hepatocellular carcinoma, RSK2 (encoded by the related RPS6KA3 gene) functions as a tumor suppressor, with inactivating mutations cooperating with AXIN1 or β-catenin alterations to promote hepatocarcinogenesis 2. Conversely, RSK3 can promote malignant transformation by switching cell fate from TGFβ-induced senescence to malignant progression through inhibition of the NF-κB pathway and prevention of proteasome-mediated IκBα degradation 3. In mammary tissue, RSK2 maintains estrogen homeostasis by acting as a negative regulator of ERK1/2 activity while positively regulating translation 1. The gene also contributes to hepatic differentiation of liver progenitor cells, with miRNA-mediated targeting of RPS6KA2 promoting this process 4. Genetic variations in RPS6KA2 are associated with colorectal cancer risk and may contribute to CIMP+ and KRAS2-mutated tumors 5. Additionally, RPS6KA2 downregulation is observed in hypertrophic cardiomyopathy, particularly in endothelial cells 6.