Biopolym. Cell. 2013; 29(3):207-214.
http://dx.doi.org/10.7124/bc.00081A
Reviews
PI3K/mTOR/S6K signaling pathway – new players and new functional links
1Filonenko V. V.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680

Abstract

This review summarizes experimental data related to the studies of PI3K/mTOR/S6K signaling conducted at the department of cell signaling. Analysis of novel S6Ks protein-protein interactions provided valuable information for understanding molecular mechanisms of regulation of S6Ks functional activity and subcellular localization mediated by PKC, CK2 and ROC1 ubiquitin ligase. We discuss the identification and functional analysis of novel isoform of ribosomal protein S6 kinase – S6K2 and of mTOR kinase – mTOR, as well as their oncogenic properties. Identification of CoA synthase responsible for last two steps in CoA biosynthesis and characterization of its interactions with S6K1 and other signaling molecules uncovere a potential link between mTOR/S6K signaling pathway and energy metabolism through regulation of CoA biosynthesis. The data concerning new molecular mechanisms of CoA synthase regulation are presented.
Keywords: PI3K/mTOR/S6K, cell signaling, protein-protein interactions, S6 kinase, CoA synthase
Full text: (PDF, in English)

References

[1] Laplante M., Sabatini D. M. mTOR signaling in growth control and disease Cell 2012 149, N 2:274–293.
[2] Fenton T. R., Gout I. T. Functions and regulation of the 70 kDa ribosomal S6 kinases Int. J. Biochem. Cell. Biol 2011 43, N 1:47–59.
[3] Gout I., Minami T., Hara K., Tsujishita Y., Filonenko V., Waterfield M. D., Yonezawa K. Molecular cloning and characterization of a novel p70 S6 kinase, p70 kinase beta containing a prolinrich region J. Biol. Chem 1998 273, N 46:30061–30064.
[4] Koh H., Jee K., Lee B., Kim J., Kim D., Yun Y. H., Kim J. W., Choi H. S., Chung J. Cloning and characterization of a nuclear S6 kinase. S6 kinase-related kinase (SRK); a novel nuclear target of Akt Oncogene 1999 18, N 36:5115–5119.
[5] Lee-Fruman K. K., Kuo C. J., Lippincott J., Terada N., Blenis J. Characterization of S6K2, a novel kinase homologous to S6K1 Oncogene 1999 18, N 36:5108–5114.
[6] Saitoh M., ten Dijke P., Miyazono K., Ichijo H. Cloning and characterization of p70(S6K beta) defines a novel family of p70 S6 kinases Biochem. Biophys. Res. Commun 1998 253, N 2:470–476.
[7] Shima H., Pende M., Chen Y., Fumagalli S., Thomas G., Kozma S. C. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase EMBO J 1998 17, N 22:6649–6659.
[8] Valovka T. I., Gout I. T., Filonenko V. V. Effect of point mutations of regulatory aminoacids residues and N- and C-terminal deletions of S6K1 and S6K2 on kinase activity Biopolym. Cell 2005 21, N 1:42–47.
[9] Valovka T. I., Fiionenko V. V., Palchevsky S. S., Velikiy M. M., Drobot L. B., Waterfield M., Matsuka G. Kh., Gout I. T. Functional and regulatory properties of p70S6 kinase b Biopolym. Cell 1999 15, N 5:415–421.
[10] Val'ovka T. I., Filonenko V. V., Velykyi M. M., Drobot L. B., Voterfill M., Matsuka H. Kh., Hut I. T. Features of fibronectin-dependent activation of ribosomal protein S6 kinase (S6K1 and S6K2) Ukr. Biokhim. Zh 2000 72, N 3:31–37.
[11] Pogrebnoy P. V., Kukharenko A. P., Tykhonkova I. A., Pal'chevskii S. S., Savinskayya L. A., Pogrebnaya A. P., Valevka T. I., Markeeva N. V., Soldatkina M. A., Matsuka G. K., Gout I. T., Filonenko V. V. Generation and characterization of monoclonal antibodies to P70S6 kinase alpha Exp. Oncol 1999 21, N 3–4:232–238.
[12] Savinska L., Skorokhod O., Klipa O., Gout I., Filonenko V. Development of monoclonal antibodies specific to ribosomal protein S6 kinase 2 Hybridoma 2012 31, N 4:289–294.
[13] Savinska L. O., Klipa O. M., Demchuk N. O., Ovcharenko G. V., Malanchuk O. M., Tykhonkova I. O., Palchevskyy S. S., Filonenko V. V. Generation of monoclonal antibodies specific to ribosomal protein S6 kinase 1 Biopolym. Cell 2012 28, N 6:424–428.
[14] Savinska L. O., Kijamova R. G., Pogrebnoy P. V., Ovcharenko G. V., Gout I. T., Filonenko V. V. Comparative characterization of S6 kinase a and b isoforms expression in mammalian tissues Biopolym. Cell 2001 17, N 5:374–379.
[15] Savinskaya L. A., Usenko V. S., Lyzogubov V. V., Pogrebnoy P. V., Pal'chevsky S. S., Ovcharenko G. V., Cheshuk V. S., Gout I. T., Matsuka G. Kh., Filonenko V. V. P 70 S6 kinase a and b isoforms expression in cell lines and breast tumors Biopolym. Cell 2003 19, N 1:64–70.
[16] Barlund M., Monni O., Kononen J., Cornelison R., Torhorst J., Sauter G., Kallioniemi OLLI-P., Kallioniemi A. Multiple genes at 17q23 undergo amplification and overexpression in breast cancer Cancer Res 2000 60, N 19:5340–5344.
[17] Savinska L. O., Lyzogubov V. V., Usenko V. S., Ovcharenko G. V., Gorbenko O. N., Rodnin M. V., Vudmaska M. I., Pogribniy P. V., Kyyamova R. G., Panasyuk G. G., Nemazanyy I. O., Malets M. S., Palchevskyy S. S., Gout I. T., Filonenko V. V. Immunohistochemical analysis of S6K1 and S6K2 expression in human breast tumors Exp. Oncol 2004 26, N 1:24–30.
[18] Lytvyn D. I., Dudchenko T. M., Lyzogubov V. V., Usenko V. S., Nespryadko S. V., Vinnitskaya A. B., Vorobyova L. I., Pal'chevskiy S. S., Filonenko V. V., Pogrebnoy P. V. Expression of aand b-isoform of p70S6 kinase in human endometrial tumors Exp. Oncol 2003 25, N 4:274–278.
[19] Lysogubov V. V., Usenko V. S., Khojaenko Yu. S., Lytvyn D. I., Soldatkina M. A., Rodnin N. V., Filonenko V. V., Pogrebniy P. V. Immunohistochemical analysis of p70S6 kinase a in human thyroid tissue upon pathology Exp. Oncol 2003 25, N 4:304–306.
[20] Lytvyn D. I., Dudchenko T. N., Filonenko V. V., Savinskaya L. A., Pogrebnoy P. V. Expression of p70S6 kinase in Guerin's carcinoma cells upon tumor development Exp. Oncol 2003 25, N 2:149–151.
[21] Filonenko V. V., Tytarenko R., Azatjan S. K., Savinska L. O., Gaydar Y. A., Gout I. T., Usenko V. S., Lyzogubov V. V. Immunohistochemical analysis of S6K1 and S6K2 localization in human breast tumors Exp. Oncol 2004 26, N 4:294–299.
[22] Lyzogubov V., Khozhaenko Y., Usenko V., Antonjuk S., Ovcharenko G., Tikhonkova I., Filonenko V. Immunohistochemical analysis of Ki-67, PCNA and S6K1/2 expression in human breast cancer Exp. Oncol 2005 27, N 2:141–144.
[23] Lyzogubov V. V., Lytvyn D. I., Dudchenko T. M, Lubchenko N. V., Pogrybniy P. V., Nespryadko S. V., Vinnitska A. B., Usenko V. S., Gout I. T., Filonenko V. V. Imunnohistochemical study of S6K1 and S6K2 expression in human endometrial adenocarcinomas Exp. Oncol 2004 26, N 4:287–293.
[24] Khoruzhenko A., Kukharchuk V., Cherednyk O., Tykhonkova I., Ovcharenko G., Malanchuk O., Filonenko V. Monoclonal antibodies to Ki-67 protein suitable for immunohistochemical analysis Hybridoma (Larchmt) 2010 29, N 4:301–304.
[25] Khoruzhenko A. I., Cherednyk O. V., Filonenko V. V. Subcellular localization of S6K1 and S6K2 forms of ribosomal protein S6 kinase in rat thyrocytes under conditions of twoand threedimensional culture Biopolym. Cell 2008 24, N 6: 470–475.
[26] Khoruzhenko A. I., Cherednyk O. V., Filonenko V. V. Subcellular localization of S6K1 and S6K2 forms of ribosomal protein S6 kinase in primary monolayer culture of rat thyrocytes Biopolym. Cell 2008 24, N 1:35–40.
[27] Pardo O. E., Wellbrock C., Khanzada U. K., Aubert M., Arozarena I., Davidson S., Bowen F., Parker P. J., Filonenko V. V., Gout I. T., Sebire N., Marais R., Downward J., Seckl M. J. FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKC epsilon, B-Raf and S6K2 EMBO J 2006 25, N 13:3078–3088.
[28] Valovka T., Verdier F., Cramer R., Zhyvoloup A., Fenton T., Rebholz H., Wang M. L., Gzhegotsky M., Lutsyk A., Matsuka G., Filonenko V., Wang L., Proud C. G., Parker P. J., Gout I. T. Protein kinase C phosphorylates ribosomal protein S6 kinase beta II and regulates its subcellular localization Mol. Cell. Biol 2003 23, N 3:852–863.
[29] Panasyuk G., Nemazanyy I., Filonenko V., Zhyvoloup A. Largescale yeast transformation in low-percentage agarose medium Biotechniques 2004 36, N 1:40–42.
[30] Zhyvoloup O. M., Nemazanyy I. O., Pobigailo N. V., Panasyuk G. G., Palchevskyy S. S., Kuharenko O. P., Savinska L O., Ovcharenko G. V., Vudmaska M. I., Gout I. T., Matsuka G. Kh., Filonenko V. V. Use of yeast two-hybrid system in search of S6K1 and S6K2 binding partners Biopolym. Cell 2002 18, N 2 102–109.
[31] Panasyuk G. G., Nemzanyy I. O., Zhyvoloup A. M., Filonenko V. V., Gout I. T. The beta subunit of casein kinase 2 as a novel binding partner of the ribosomal protein S6 kinase 1 Biopolym. Cell 2005 21, N 5:407–412.
[32] Panasyuk G., Nemazanyy I., Zhyvoloup A., Bretner M., Litchfield D. W., Filonenko V., Gout I. T. Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17 J. Biol. Chem 2006 281, N 42:31188–31201.
[33] Panasyuk G. G., Nemazanyy I. O., Zhyvoloup A. M., Filonenko V. V., Gout I. T. Regulation of S6K1 subcellular localization by Casein kinase 2 Biopolym. Cell 2006 22, N 1:82–84.
[34] Wang M. L., Panasyuk G., Gwalter J., Nemazanyy I., Fenton T., Filonenko V., Gout I. Regulation of ribosomal protein S6 kinases by ubiquitination Biochem. Biophys. Res. Commun 2008 369, N 2:382–387.
[35] Panasyuk G., Nemazanyy I., Filonenko V., Gout I. Ribosomal protein S6 kinase 1 interacts with and is ubiquitinated by ubiquitin ligase ROC1 Biochem. Biophys. Res. Commun 2008 369, N 2:339–343.
[36] Rebholz H., Panasyuk G., Fenton T., Nemazanyy I., Valovka T., Flajolet M., Ronnstrand L., Stephens L., West A., Gout I. T. Receptor association and tyrosine phosphorylation of S6 kinases FEBS J 2006 273, N 9:2023–2036.
[37] Panasyuk G. G., Nemazanyy I. O., Gout I. T., Filonenko V. V. Identification of endogeneous isoform of ribosomal protein S6 kinase – S6K2 Biopolym. Cell 2005 21, N 3:293–295.
[38] Zhyvoloup A., Nemazanyy I., Babich A., Panasyuk G., Pobigailo N., Vudmaska M., Naidenov V., Kukharenko O., Palchevskii S., Savinska L., Ovcharenko G., Verdier F., Valovka T., Fenton T., Rebholz H., Wang M. L., Shepherd P., Matsuka G., Filonenko V., Gout I. T. Molecular cloning of CoA synthase. The missing link in CoA biosynthesis J. Biol. Chem 2002 277, N 25:22107–22110.
[39] Nemazanyy I., Panasyuk G., Zhyvoloup A., Panayotou G., Gout I. T., Filonenko V. Specific interaction between S6K1 and CoA synthase: a potential link between the mTOR/S6K pathway, CoA biosynthesis and energy metabolism FEBS Lett 2004 578, N 3:357–362.
[40] Zhyvoloup A., Nemazanyy I., Panasyuk G., Valovka T., Fenton T., Rebholz H., Wang M. L., Foxon R., Lyzogubov V., Usenko V., Kyyamova R., Gorbenko O., Matsuka G., Filonenko V., Gout I. T. Subcellular localization and regulation of Coenzyme A Synthase J. Biol. Chem 2003 278, N 50:50316–50321.
[41] Nemazanyy I., Panasyuk G., Breus O., Zhyvoloup A., Filonenko V., Gout I. T. Identification of a novel CoA synthase isoform, which is primarily expressed in the brain Biochem. Biophys. Res. Commun 2006 341, N 4:995–1000.
[42] Breus O. S., Panasyuk G. G., Gout I. T., Filonenko V. V., Nemazanyy I. O. Proline rich regions of coenzyme A synthase a and b interact with SH3 domains of signaling proteins in vitro Biopolym. Cell 2008 24, N 2:123–128.
[43] Breus O., Panasyuk G., Gout I. T., Filonenko V., Nemazanyy I. CoA synthase is in complex with p85alphaPI3K and affects PI3K signaling pathway Biochem. Biophys. Res. Commun 2009 385, N 4:581–585.
[44] Breus O., Panasyuk G., Gout I. T., Filonenko V., Nemazanyy I. CoA Synthase is phosphorylated on tyrosines in mammalian cells, interacts with and is dephosphorylated by Shp2PTP Mol. Cell. Biochem 2010 335, N 1–2:195–202.
[45] Breus O S., Nemazanyy I. O., Gout I. T., Filonenko V. V., Panasyuk G. G. CoA Synthase influences adherence-independent growth and survival of mammalian cells in vitro Biopolym. Cell 2009 25, N 5:384–389.
[46] Gudkova D., Panasyuk G., Nemazanyy I., Zhyvoloup A., Monteil P., Filonenko V., Gout I. EDC4 interacts with and regulates the dephospho-CoA kinase activity of CoA synthase FEBS Lett 2012 586, N 20:3590–3595.
[47] Gudkova D. O., Panasyuk G. G., Nemazanyy I. O., Filonenko V. V. PI3K/mTor-dependent signaling pathway as a possible regulator of processing body assembly Biopolym. Cell 2011 27, N 5:369–372.
[48] Gudkova D. O., Panasyuk G. G., Nemazanyy I. O., Filonenko V. V. Novel antibodies against RCD-8 as a tool to study processing bodies Biopolym. Cell 2010 26, N 6:512–516.
[49] Panasyuk G., Nemazanyy I., Zhyvoloup A., Filonenko V., Davies. D, Robson M., Pedley R. B., Waterfield M., Gout I. The mTORbeta splicing isoform promotes cell proliferation and tumorigenesis J. Biol. Chem 2009 284, N 45:30807–30814.
[50] Skorokhod O., Nemazanyy I., Breus O., Filonenko V., Panasyuk G. Generation and characterization of monoclonal antibodies to TDRD7 protein Hybridoma (Larchmt) 2008 27, N 3:211–216.
[51] Malanchuk O. M., Palchevskyy S. S., Pozur V. K., Gout I. T., Filonenko V. V. Interaction of serine/threonine protein phosphatase 5 (PP5) with the protein product of tumour suppressor gene Tsc2 Biopolym. Cell 2007 23, N 4:318–323.
[52] Malanchuk O., Palchevskyy S., Ovcharenko G., Gwalter J., Pozur V., Gout I., Filonenko V. Generation and characterization of monoclonal antibodies against tuberous sclerosis complex 2 Hybridoma (Larchmt) 2007 26, N 4:259–266.
[53] Malanchuk O. M., Palchevskyy S. S., Filonenko V. V. Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 Biopolym. Cell 2008 24, N 2:176–179.
[54] Gout I., Middleton G., Adu J., Ninkina N. N., Drobot L. B., Filonenko V., Matsuka G., Davies A. M., Waterfield M., Buchman V. L. Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein EMBO J 2000 19, N 15:4015–4025.
[55] DeBerardinis R. J., Lum J. J., Hatzivassiliou G., Thompson C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation Cell Metab 2008 7, N 1:11–20.
[56] Gorbenko O. M., Panayotou D., Volkova D. D., Zhyvoloup O. M., Kukharenko O. P., Gout I. T., Filonenko V. V. Interaction of fatty acid transporting protein FABP4 with phosphatase PTEN Biopolym. Cell 2006 22, N 3:217–224.
[57] Gorbenko O., Panayotou G., Zhyvoloup A., Volkova D., Gout I. Filonenko V. Identification of novel PTEN-binding proteins: PTEN interections with fatty acid binding protein FABP4 Mol. Cell. Biochem 2010 337, N 1–2:299–305.
[58] Gorbenko O., Filonenko V., Gout I. Generation and characterization of monoclonal antibodies against FABP4 Hybridoma (Larchmt) 2006 25, N 2:86–90.
[59] Uysal K. T., Scheja L., Wiesbrock S. M., Bonner-Weir S., Hotamisligil G. S. Improved glucose and lipid metabolism in genetically obese mice lacking aP2 Endocrinology 2000 141, N 9:3388–3396.