Biopolym. Cell. 2015; 31(1):5-14.
Обзоры
Характеристика mTOR сигнального пути и его привлечения к регуляции клеточной подвижности путем реконструкции архитектуры цитоскелета
1Косач В. Р., 1Чередник О. В., 1Хоруженко А. И.
  1. Институт молекулярной биологии и генетики НАН Украины
    ул. Академика Заболотного, 150, Киев, Украина, 03680

Abstract

mTOR киназa является одним из основных звеньев, расположенных на пересечении нескольких путей внутриклеточной передачи сигнала. Дерегуляция сигналинга mTOR киназы сопровождает развитие онкологических заболеваний, диабета, нейродегенеративных расстройств и старения. При­менение ингибитора mTOR рапамицина снижает уровень миграции и инвазии злокачественных клеток и образование метастазов. Однако, точный механизм регуляции подвижности клеток mTOR киназы полностью не изучен. Эта статья посвященна последним исследованиям, которые демонстрируют возможную роль mTOR киназы в регуляции ремоделирования цитоскелета и миграции клеток. Под­роб­ные исследования этой неканонической функции mTOR киназы позволят расширить наши знания о миграции клеток и образование метастазов и может привести к улучшению противораковых терапевтических подходов.
Keywords: mTOR сигналинг, рапамицин, перестройка цитоскелета, промежуточные филаменты, микротрубочки, метастазирование

References

[1] Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21-35.
[2] Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013;123(3):980-9.
[3] Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2(8):563-72.
[4] Hong SM, Park CW, Cha HJ, Kwon JH, Yun YS, Lee NG, Kim DG, Nam HG, Choi KY. Rapamycin inhibits both motility through down-regulation of p-STAT3 (S727) by disrupting the mTORC2 assembly and peritoneal dissemination in sarcomatoid cholangiocarcinoma. Clin Exp Metastasis. 2013;30(2):177-87.
[5] Feng W, Jia S. Rapamycin inhibits the invasive ability of thyroid cancer cells by down-regulating the expression of VEGF-C in vitro. Cell Biochem Funct. 2012;30(6):487-91.
[6] Lodish H, Arnold B, Kaiser Chris, Monty K. Molecular Cell Biology. New York: W. H. Freeman, 2012; 973 p.
[7] Zhou H, Huang S. Role of mTOR signaling in tumor cell motility, invasion and metastasis. Curr Protein Pept Sci. 2011;12(1):30-42.
[8] Laplante M, Sabatini DM. mTOR Signaling. Cold Spring Harb Perspect Biol. 2012;4(2). pii: a011593.
[9] Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature. 2013;497(7448):217-23.
[10] Hall MN. Talks about TORCs: recent advancesin target of rapamycin signalling. On mTOR nomenclature. Biochem Soc Trans. 2013;41(4):887-8.
[11] Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-93.
[12] Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell. 2010;38(5):768-74.
[13] Manfredi GI, Dicitore A, Gaudenzi G, Caraglia M, Persa­ni L, Vitale G. PI3K/Akt/mTOR signaling in medullary thyroid cancer: a promising molecular target for cancer therapy. Endocrine. 2015;48(2):363–70.
[14] Follo MY, Manzoli L, Poli A, McCubrey JA, Cocco L. PLC and PI3K/Akt/mTOR signalling in disease and cancer. Adv Biol Regul. 2015;57:10-6.
[15] Efeyan A, Zoncu R, Sabatini DM. Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med. 2012;18(9):524-33.
[16] Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340(6136):1100-6.
[17] Filonenko VV. PI3K/mTOR/S6K signaling pathway – new pla­yers and new functional links. Biopolym Cell. 2013;29 (3):207–14.
[18] 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(2):141-4.
[19] Filonenko VV, Tytarenko R, Azatjan SK, Savinska LO, Gaydar YA, Gout IT, Usenko VS, Lyzogubov VV. Immunohistochemical analysis of S6K1 and S6K2 localization in human breast tumors. Exp Oncol. 2004;26(4):294-9.
[20] Oh WJ, Jacinto E. mTOR complex 2 signaling and functions. Cell Cycle. 2011;10(14):2305-16.
[21] Jacinto E, Loewith R, Schmidt A, Lin S, R?egg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122-8.
[22] Sen B, Xie Z, Case N, Thompson WR, Uzer G, Styner M, Rubin J. mTORC2 regulates mechanically induced cytoskeletal reorganization and lineage selection in marrow-derived mesenchymal stem cells. J Bone Miner Res. 2014;29(1):78-89.
[23] Magin TM, Vijayaraj P, Leube RE. Structural and regulatory functions of keratins. Exp Cell Res. 2007;313(10):2021-32.
[24] Chang L, Goldman RD. Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol. 2004;5(8):601-13.
[25] Sihag RK, Inagaki M, Yamaguchi T, Shea TB, Pant HC. Role of phosphorylation on the structural dynamics and function of types III and IV intermediate filaments. Exp Cell Res. 2007;313(10):2098-109.
[26] Seltmann K, Roth W, Kr?ger C, Loschke F, Lederer M, H?ttelmaier S, Magin TM. Keratins mediate localization of hemidesmosomes and repress cell motility. J Invest Dermatol. 2013;133(1):181-90.
[27] Ivaska J, Pallari HM, Nevo J, Eriksson JE. Novel functions of vimentin in cell adhesion, migration, and signaling. Exp Cell Res. 2007;313(10):2050-62. .
[28] Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature. 2006;441(7091):362-5.
[29] Vijayaraj P, Kr?ger C, Reuter U, Windoffer R, Leube RE, Magin TM. Keratins regulate protein biosynthesis through localization of GLUT1 and -3 upstream of AMP kinase and Raptor. J Cell Biol. 2009;187(2):175-84.
[30] Hickerson RP, Leake D, Pho LN, Leachman SA, Kaspar RL. Rapamycin selectively inhibits expression of an inducible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients. J Dermatol Sci. 2009;56(2):82-8.
[31] Izawa I, Inagaki M. Regulatory mechanisms and functions of intermediate filaments: a study using site- and phosphorylation state-specific antibodies. Cancer Sci. 2006;97(3):167-74.
[32] Lewin B. Cells. MA: Jones & Bartlett Learning. 2007. 863 p.
[33] Liu L, Chen L, Chung J, Huang S. Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. Oncogene. 2008;27(37):4998-5010.
[34] Goncharova EA, James ML, Kudryashova TV, Goncharov DA, Krymskaya VP. Tumor suppressors TSC1 and TSC2 differentially modulate actin cytoskeleton and motility of mouse embryonic fibroblasts. PLoS One. 2014;9(10):e111476.
[35] Ohsawa M, Kobayashi T, Okura H, Igarashi T, Mizuguchi M, Hino O. TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLoS One. 2013;8(1):e54503.
[36] Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, Lee EY, Weiss HL, O'Connor KL, Gao T, Evers BM. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011;71(9):3246-56.
[37] Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD, Horng T. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun. 2013;4:2834.
[38] He Y, Li D, Cook SL, Yoon MS, Kapoor A, Rao CV, Kenis PJ, Chen J, Wang F. Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol Biol Cell. 2013;24(21):3369-80.
[39] Josselyn SA, Frankland PW. mTORC2: actin on your memory. Nat Neurosci. 2013;16(4):379-80.
[40] Angliker N, R?egg MA. In vivo evidence for mTORC2-mediated actin cytoskeleton rearrangement in neurons. Bioarchitecture. 2013;3(4):113-8.
[41] Berven LA, Willard FS, Crouch MF. Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Exp Cell Res. 2004;296(2):183-95.
[42] Mendes Sdos S, Candi A, Vansteenbrugge M, Pignon MR, Bult H, Boudjeltia KZ, Munaut C, Raes M. Microarray analyses of the effects of NF-kappaB or PI3K pathway inhibitors on the LPS-induced gene expression profile in RAW264.7 cells: synergistic effects of rapamycin on LPS-induced MMP9-overexpression. Cell Signal. 2009;21(7):1109-22.
[43] Zhou HY, Wong AS. Activation of p70S6K induces expression of matrix metalloproteinase 9 associated with hepatocyte growth factor-mediated invasion in human ovarian cancer cells. Endocrinology. 2006;147(5):2557-66.
[44] Choi JH, Adames NR, Chan TF, Zeng C, Cooper JA, Zheng XF. TOR signaling regulates microtubule structure and function. Curr Biol. 2000;10(14):861-4.
[45] Malik AR, Urbanska M, Macias M, Skalecka A, Jaworski J. Beyond control of protein translation: what we have lear­ned about the non-canonical regulation and function of mammalian target of rapamycin (mTOR). Biochim Bio­phys Acta. 2013;1834(7):1434–48.
[46] Zhou Q, Wong CH, Lau CP, Hui CW, Lui VW, Chan SL, Yeo W. Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma. Int J Hepatol. 2013;2013:103830.
[47] Barnes EA, Kenerson HL, Jiang X, Yeung RS. Tuberin regulates E-cadherin localization: implications in epithelial-mesenchymal transition. Am J Pathol. 2010;177(4):1765-78.
[48] Clippinger AJ, Alwine JC. Dynein mediates the localization and activation of mTOR in normal and human cytomegalovirus-infected cells. Genes Dev. 2012;26(18):2015-26.
[49] Vazquez-Martin A, Sauri-Nadal T, Menendez OJ, Oliveras-Ferraros C, Cuf? S, Corominas-Faja B, L?pez-Bonet E, Menendez JA. Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis. Cell Cycle. 2012;11(22):4211-21.
[50] 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(4):301-4.