S6 Kinases

S6 Kinases

Definition
A family of ribosomal protein S6 kinases (S6K) that are considered the major physiological kinases for ribosomal protein S6. Ribosomal S6K are involved in signal transduction.

Discovery
40S ribosomal protein S6 phosphorylation was first described 25 years ago by Gressner and Wool in 1974 1. It has been implicated in the translational up-regulation of mRNAs coding for the components of protein synthetic apparatus 2. These mRNAs contain an oligopyrimidine tract at their 5' transcriptional start site, termed a 5'TOP, which has been shown to be essential for their regulation at the translational level 3.The direct upstream elements involved in growth factor-induced kinase activation were also identified. Use of the immunosuppressant rapamycin, a bacterial macrolide, in conjunction with dominant interfering and activated forms of S6K1 has helped to establish the role of this signaling cascade in the regulation of growth and proliferation4. In addition, current studies employing the mouse as well as Drosophila melanogaster have provided new insights into physiological function of S6K in the animal.

Structural Characteristics
Activation of S6K is brought about by the phosphorylation in a hierarchical manner of key residues, which reside within distinct regulatory domains5. The kinase has a short amino terminus, containing an acidic domain, which confers rapamycin sensitivity. The catalytic domain, containing the eleven conserved domains found in all Serine and Threonine protein kinases, follows this segment. The catalytic domain is followed by a linker domain, which couples the catalytic domain with an auto-inhibitory domain 5. The linker domain was found to be conserved in all the kinases of the Protein A, G and C (AGC) family of Serine/Threonine kinases. Immediately, downstream of the auto-inhibitory domain is the amino terminus, which has been implicated in the interaction of the kinase with other proteins, such as neurabin or spinophilin 6.

Mode of Action
Activation of S6K1 requires phosphorylation of four S/T-P sites, which reside in the auto inhibitory domain. This event, in combination with phosphorylation of S371 in the linker domain, facilitates T389 phosphorylation, which also resides in the linker domain, and provides a docking site for the phosphoinositide-dependent protein kinase, (PDK1). PDK1 docks on T389 and phosphorylation of S371 in the linker domain, and provides a docking site for the PDK1. PDK1 docks on T389 and phosphorylates T229 in the activation loop of the kinase, leading to kinase activation. The critical event then in activating S6K is phosphorylation of T389. A number of kinases have been suggested as potential T389 kinases, including protein kinase B, PDK1 and the NIMA related kinases NEK6 and 7. The mammalian Target of Rapamycin, mTOR, is a potent T389 kinase. mTOR is a member of the PI3K related family of protein kinases, which also includes ATM, ATR and DNA dependent kinases. The latter three are all involved in DNA damage repair, whereas mTOR acts as an amino acid and energy. If either amino acids, especially branch-chain amino acids, or ATP levels drop, mTOR activity decreases leading to inhibition of S6K1 7.

Functions
In expression of hormones and growth factors, S6K has been implicated in the expression of a number of growth factors and hormones, including insulin and insulin-like growth factor 2. Mutation in S6K1 or downstream effectors can contribute together with genetic and environmental factors to specific forms of diabetes 7.

Development and growth control, Loss of dS6K function in Drosophila melanogaster demonstrated its paramount importance in development and growth control, whereas deletion of the S6K1 gene in the mouse led to an animal of reduced size and the identification of the S6K1 homologue, S6K2. Such mice are significantly smaller during fetal development and hypoinsulinemic in the adult, conditions known to lead to type 2 diabetes 8.

Insulin activation, S6 kinase is activated by insulin through promoting phosphorylation of a specific serine/threonine residues on the enzyme polypeptide, by activating an serine/threonine protein kinase distinct from microtubule-associated protein 2 kinase 9.

References
1.Gressner AM, Wool IG (1974). The phosphorylation of liver ribosomal proteins in vivo: Evidence that only a single small subunit (S6) is phosphorylated. J Biol Chem., 249:6917-6925.
2.Fumagalli S (2000). S6 phosphorylation and signal transduction. In Sonenberg N, Hershey JWB, Mathews M (eds) Translational control of gene expression. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, 695-717.
3.Meyuhas O (1996). Translational control of ribosomal protein mRNAs in eukaryotes. In: Hershey JWB, Mathews MB, Sonenberg N (eds) Translational Control. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 363-388
4.Dennis PB, Thomas G (2002). Quick guide: target of rapamycin. Curr Biol., 12:R269.
5.Pullen N, Thomas G (1997). The modular phosphorylation and activation of p70s6k. FEBS Letters., 410:78-82.
6.Moser BA, Dennis PB, Pullen N, Pearson RB, Williamson NA, Wettenhall RE, Kozma SC, Thomas G (1997). Dual requirement for a newly identified phosphorylation site in p70s6k. Mol Cell Biol., 17:5648-5655.
7.Thomas G (2002). The S6 kinase signaling pathway in the control of development and growth. Biological Research, 35(2):305-313.
8.Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, Klumperman J, Thorens B, Thomas G (2000). Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature, 408:994-997.
9.Price DJ, Gunsalus JR, Avruch J (1990). Insulin activates a 70-kDa S6 kinase through serine/threonine-specific phosphorylation of the enzyme polypeptide. PNAS., 87(20):7944–7948.

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