p70S6K1

p70 S6 kinase 1 (p70S6K1), also known as S6K1, is a serine/threonine protein kinase in the AGC family. It serves as a major downstream effector of the mechanistic target of rapamycin complex 1 (mTORC1) and links nutrient and growth factor signals to protein synthesis and cell growth. The human enzyme is encoded by the RPS6KB1 gene and is one of the best-characterized mediators of mTOR signaling.

Activation and regulation of p70S6K1 occur through a two-step phosphorylation process driven by mTORC1. mTORC1 phosphorylates a hydrophobic motif (Thr389), which enables subsequent phosphorylation in the activation loop (Thr229) by PDK1 and/or autophosphorylation, yielding full kinase activity. The activity of S6K1 is sensitive to rapamycin, an inhibitor of mTORC1. In addition, S6K1 participates in a negative feedback loop by phosphorylating IRS-1, contributing to downregulation of PI3K–Akt signaling.

Function and substrates: Activated p70S6K1 phosphorylates the ribosomal protein S6 (Ser235/236 in humans) to promote translation of 5′ TOP mRNAs and overall protein synthesis. It also targets other translation-related proteins such as eIF4B and PDCD4, reinforcing cap-dependent translation and ribosome biogenesis. Through these actions, S6K1 influences cell growth, size, metabolism, and proliferative capacity.

Clinical relevance: Dysregulation of S6K1 signaling is linked to cancer and metabolic disorders. Because it sits downstream of mTORC1, S6K1 activity reflects mTOR pathway status and is a focal point for therapeutic strategies, though compensatory pathways can affect outcomes of pathway-targeted interventions.

Structure and interactions: S6K1 contains a catalytic kinase domain and regulatory regions including a hydrophobic motif and a TOS motif that facilitates interaction with mTORC1 components such as RAPTOR, integrating signals from the nutrient-sensing network.