The nuts‐and‐bolts of ribosomal protein s6 kinase 1 regulation: A shared responsibility for mTOR complexes 1 and 2

Ribosomal protein S6 kinase 1 (S6K1) is a master regulator of cell growth and metabolism and a primary effector of the mTOR signaling pathway. Given its central role in cancer and metabolic diseases, S6K1 is a high-priority therapeutic target; however, developing effective treatments requires a definitive understanding of how the enzyme is activated. This review provides a comprehensive synthesis of S6K1 biology, covering its structural domains, various chemical modifications like acetylation and ubiquitination, and its regulation by noncoding RNAs. We specifically highlight the transition from traditional 'canonical' models to an emerging 'non-canonical' paradigm. Central to this shift is the proposal that S6K1 activation is a shared responsibility between two complexes: mTORC1 and mTORC2. We detail a two-step mechanism where mTORC1 first 'primes' the enzyme by relieving internal constraints, allowing mTORC2 to complete the activation process. By reconciling these different models and addressing long-standing questions about drug sensitivity, this review establishes a modern framework for S6K1 biology and identifies new opportunities for precise therapeutic intervention.