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Wednesday 26 January 2005

RPS6KB1 mediates the rapid phosphorylation of ribosomal protein S6 (MIM.180460) on multiple serine residues in response to insulin or several classes of mitogens.


The mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) signaling pathways promote cell growth and cell cycle progression in response to nutritional, energy, and mitogenic cues.

The ribosomal protein S6 kinases, RPS6KB1 (S6K1) and RPS6KB2 (S6K2), lie downstream of mTOR and PI3K, suggesting that translational control through the phosphorylation of RPS6 (S6) regulates cell growth.

Genetic experiments predict that a substrate that is specific to S6K1 but not S6K2 regulates cell growth.

TSC/mTOR signaling pathway

TSCs (TSC1 and TSC2) receive input from several signalling pathways, including the PI3K–Akt (insulin-signalling) pathway, the ERK1/2 pathway, the p38MAPK–MK2 pathway and the LKB1–AMPK (energy-sensing) pathway, as well as GSK3β. Also, there is probably direct input from signalling in response to hypoxia.

In response to these signals, TSC1–2 acts as a GTPase-activating protein (GAP) for Rheb, which, in turn, regulates mTOR. Activated mTOR has two main downstream targets, RPS6KB1 (S6K1) and 4E-BP1. This process activates cell growth and proliferation.

mTOR exists in two complexes: mTOR Complex1, which is rapamycin-sensitive and phosphorylates S6K1 and initiation factor 4E binding proteins (4E-BPs), and mTOR Complex2, which is rapamycin-insensitive and phosphorylates protein kinase B (PKB, also known as Akt).

Metabolic pathways

The mammalian target of rapamycin (mTOR or FRAP1) and its effector, S6 kinase 1 (S6K1 or RPS6KB1), lie at the crossroads of a nutrient-hormonal signaling network that is involved in specific pathological responses, including obesity, diabetes and cancer.

Both mTOR complexes are stimulated by mitogens, but only mTOR Complex1 is under the control of nutrient and energy inputs. Thus, to orchestrate the control of homeostatic responses, mTOR Complex1 must integrate signals from distinct cues.

See also

- TSC/mTOR signaling pathway
- PI3K/PTEN/AKT signaling pathway )phosphatidylinositol 3-kinase pathway or PI3K signaling pathway)


- Dann SG, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med. 2007 Jun;13(6):252-9. PMID: 17452018

- Richardson CJ, Broenstrup M, Fingar DC, Julich K, Ballif BA, Gygi S, Blenis J. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol. 2004 Sep 7;14(17):1540-9. PMID: 15341740