S6Ks

S6Ks, or S6 kinase proteins, are a small family of serine/threonine kinases in the AGC protein kinase superfamily that act as key mediators of the mTOR signaling pathway. They regulate protein synthesis, cell growth, and metabolism in response to nutrients, energy status, and growth factors.

In humans, the two main isoforms are S6K1 and S6K2, encoded by the RPS6KB1 and RPS6KB2 genes, respectively. S6K1 is commonly referred to as p70 S6 kinase and S6K2 as p90 S6 kinase. The two enzymes share similar domain organization, including a catalytic kinase domain and a C-terminal regulatory tail, but they can have distinct subcellular localizations and substrate preferences.

Activation of S6Ks is initiated by mTORC1-dependent phosphorylation at the hydrophobic motif within the C-terminal tail, which primes activation loop phosphorylation by PDK1, enabling full kinase activity. This process is stimulated by growth factors (such as insulin and IGF-1), amino acids, and adequate energy, and is subject to negative feedback loops that restrain insulin signaling via substrates such as IRS-1.

Functionally, S6Ks phosphorylate the ribosomal protein S6 and other targets like eIF4B, promoting translation initiation and the selective translation of 5'TOP mRNAs. They also influence other processes such as ribosome biogenesis, polysome formation, and the degradation of PDCD4, further modulating protein synthesis. S6K1 and S6K2 can have overlapping but also distinct roles; S6K1 is largely cytoplasmic and closely tied to translation control, while S6K2 has reported nuclear functions and context-dependent substrate interactions.

Clinical relevance centers on cancer and metabolic disease, where hyperactivation of S6Ks can support growth and survival. Pharmacological inhibitors targeting S6K1 (and, in some cases, S6K1/2) are under investigation, with interest in expanding therapeutic options for oncology and metabolic disorders. Genetic studies in models suggest S6K1 impacts aging and insulin sensitivity, highlighting broader physiological relevance.