Biopolym. Cell. 2005; 21(1):42-47.
Cell Biology
Effect of point mutations of regulatory aminoacids residues and N- and C-terminal deletions of S6K1 and S6K2 on kinase activity
1Valovka T. I., 1, 2Gout I. T., 2Filonenko V. V.
  1. Ludwig Institute for Cancer Research
    91 Riding house str., London, UK, WIP8BT
  2. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680

Abstract

The family of ribosomal protein S6 kinases includes two forms – S6K1 and S6K2 that share high level of structural homology towards catalytic domains. Existence of homological phosphorylation sites suggests the functioning of similar mechanisms of the kinase activation. Using site-directed mutagenesis and N-, C-terminal deleting of S6K it has been demonstrated that phosphorylation of Thr412 and Thr401 are necessary for the full activation of S61 and S62 correspondent. Different sensitivity of S6K to the inhibitory actions of rapamicine relates to the structure of C- terminal S6K regions that exhibits low homology.
Keywords: ribosomal protein 56, S6K1 and S6K2, site-directed mutagenesis

References

[1] Avruch J, Belham C, Weng Q, Hara K, Yonezawa K. The p70 S6 kinase integrates nutrient and growth signals to control translational capacity. Prog Mol Subcell Biol. 2001;26:115-54.
[2] Dufner A, Thomas G. Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res. 1999;253(1):100-9.
[3] Price DJ, Nemenoff RA, Avruch J. Purification of a hepatic S6 kinase from cycloheximide-treated Rats. J Biol Chem. 1989;264(23):13825-33.
[4] Gout I, Minami T, Hara K, Tsujishita Y, Filonenko V, Waterfield MD, Yonezawa K. Molecular cloning and characterization of a novel p70 S6 kinase, p70 S6 kinase beta containing a proline-rich region. J Biol Chem. 1998;273(46):30061-4.
[5] Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G. Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k. EMBO J. 1997;16(12):3693-704.
[6] Koh H, Jee K, Lee B, Kim J, Kim D, Yun YH, Kim JW, Choi HS, Chung J. Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt. Oncogene. 1999;18(36):5115-9.
[7] Burnett PE, Blackshaw S, Lai MM, Qureshi IA, Burnett AF, Sabatini DM, Snyder SH. Neurabin is a synaptic protein linking p70 S6 kinase and the neuronal cytoskeleton. Proc Natl Acad Sci U S A. 1998;95(14):8351-6.
[8] Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G. S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol. 2004;24(8):3112-24.
[9] Valovka T, Filonenko V, Palchevsky S, Velikiy M, Drobot L, Waterfield M, Matsuka G, Gout I. Functional and regulatory properties of p70S6 kinase ОІ. Biopolym Cell. 1999; 15(5):415-21.
[10] Dennis PB, Pullen N, Pearson RB, Kozma SC, Thomas G. Phosphorylation sites in the autoinhibitory domain participate in p70(s6k) activation loop phosphorylation. J Biol Chem. 1998;273(24):14845-52.
[11] Weng QP, Kozlowski M, Belham C, Zhang A, Comb MJ, Avruch J. Regulation of the p70 S6 kinase by phosphorylation in vivo. Analysis using site-specific anti-phosphopeptide antibodies. J Biol Chem. 1998;273(26):16621-9.
[12] Pullen N, Thomas G. The modular phosphorylation and activation of p70s6k. FEBS Lett. 1997;410(1):78-82.
[13] Alessi DR, Kozlowski MT, Weng QP, Morrice N, Avruch J. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Curr Biol. 1998;8(2):69-81.
[14] Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE, Thomas G. The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J. 1995;14(21):5279-87.
[15] Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 2004;23(18):3151-71.
[16] Weng QP, Andrabi K, Kozlowski MT, Grove JR, Avruch J. Multiple independent inputs are required for activation of the p70 S6 kinase. Mol Cell Biol. 1995;15(5):2333-40.
[17] Martin KA, Blenis J. Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv Cancer Res. 2002;86:1-39.