S6K

S6K, short for ribosomal protein S6 kinase, refers to a family of serine/threonine kinases that phosphorylate the ribosomal protein S6 and other substrates to regulate protein synthesis, cell growth, and metabolism. In humans, the two main paralogs are S6K1 and S6K2, encoded by the RPS6KA1 and RPS6KA2 genes, respectively. These kinases are evolutionarily conserved and share a catalytic kinase domain plus regulatory regions that control their activity.

S6K1 and S6K2 are activated primarily through the mTOR signaling pathway. Activation generally begins with mTOR complex 1 (mTORC1) phosphorylating the hydrophobic motif site on S6K (for S6K1 this is around Thr389), which relieves autoinhibition and enables further phosphorylation by phosphoinositide-dependent kinase-1 (PDK1) at the activation loop (Thr229). Additional phosphorylation events modulate activity and stability. S6K1 and S6K2 can also be regulated by other kinases in various contexts, and S6K1 has a distinct autoregulatory region that influences responsiveness.

Functionally, activated S6Ks phosphorylate ribosomal protein S6 and other substrates involved in translation initiation and ribosome biogenesis, promoting the translation of 5'-terminal oligopyrimidine tract (5'-TOP) mRNAs and supporting cellular growth. Beyond translation, S6Ks participate in metabolic signaling, insulin response, and cell survival, and they can contribute to feedback regulation of upstream insulin signaling.

Clinical relevance and research focus include roles in cancer, metabolic diseases, and aging. Because mTOR-S6K signaling integrates growth and nutrient signals, S6Ks are targets of therapeutic interest, with inhibitors explored in preclinical and clinical settings.