Biopolym. Cell. 2005; 21(4):299-311.
Обзоры
Сигнальный путь трансформирующего фактора роста β и его регуляция
1Федоренко А. В., 1Стойка Р. С.
  1. Институт биологии клетки НАН Украины
    ул. Драгоманова, 14/16, Львов, Украина, 79005

Abstract

Приведены современные данные о структуре и функциях лигандов, рецепторов и нисходящих эффекторных белков сиг­нального пути трансформирующего фактора роста β. Рас­смотрен механизм передачи сигнала на пути от поверхности клетки до генов-мишеней в ядре, способы их регуляции и перекрестные связи с другими сигнальными путями.
Keywords: TGFβ, рецепторы, Smad белки, сигнальный путь

References

[1] Filchenkov AA, Stoika RS, Bykorez AI. Transforming growth factors. Kiev: Naukova Dumka, 1994; 292 p.
[2] Massagu? J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753-91.
[3] de Larco JE, Todaro GJ. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A. 1978;75(8):4001-5.
[4] Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22-28;316(6030):701-5.
[5] Roberts AB, Sporn MW. The transforming growth factor-bs. Peptide Growth Factors and Their Receptors. Berlin: Springer, 1990. Pt I: 419-472.
[6] Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Bl?cker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ; International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860-921.
[7] Shi Y, Massagu? J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685-700.
[8] Massagu? J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103(2):295-309.
[9] Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29(2):117-29.
[10] Roberts AB, Sporn MB. Differential expression of the TGF-beta isoforms in embryogenesis suggests specific roles in developing and adult tissues. Mol Reprod Dev. 1992;32(2):91-8.
[11] Roberts AB, Kim SJ, Noma T, Glick AB, Lafyatis R, Lechleider R, Jakowlew SB, Geiser A, O'Reilly MA, Danielpour D, et al. Multiple forms of TGF-beta: distinct promoters and differential expression. Ciba Found Symp. 1991;157:7-15.
[12] Gaddy-Kurten D, Tsuchida K, Vale W. Activins and the receptor serine kinase superfamily. Recent Prog Horm Res. 1995;50:109-29.
[13] Spencer FA, Hoffmann FM, Gelbart WM. Decapentaplegic: a gene complex affecting morphogenesis in Drosophila melanogaster. Cell. 1982;28(3):451-61.
[14] Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242(4885):1528-34.
[15] Padgett RW, Wozney JM, Gelbart WM. Human BMP sequences can confer normal dorsal-ventral patterning in the Drosophila embryo. Proc Natl Acad Sci U S A. 1993;90(7):2905-9.
[16] Hogan BL. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev. 1996;10(13):1580-94.
[17] Massagu? J, Weis-Garcia F. Serine/threonine kinase receptors: mediators of transforming growth factor beta family signals. Cancer Surv. 1996;27:41-64.
[18] Miyazono K, Ichijo H, Heldin CH. Transforming growth factor-beta: latent forms, binding proteins and receptors. Growth Factors. 1993;8(1):11-22.
[19] Sun PD, Davies DR. The cystine-knot growth-factor superfamily. Annu Rev Biophys Biomol Struct. 1995;24:269-91.
[20] Munger JS, Harpel JG, Gleizes PE, Mazzieri R, Nunes I, Rifkin DB. Latent transforming growth factor-beta: structural features and mechanisms of activation. Kidney Int. 1997;51(5):1376-82.
[21] Munger JS, Harpel JG, Giancotti FG, Rifkin DB. Interactions between growth factors and integrins: latent forms of transforming growth factor-beta are ligands for the integrin alphavbeta1. Mol Biol Cell. 1998;9(9):2627-38.
[22] Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell. 1998;93(7):1159-70.
[23] Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163-76.
[24] Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature. 1990;346(6281):281-4.
[25] Mather JP. Follistatins and alpha 2-macroglobulin are soluble binding proteins for inhibin and activin. Horm Res. 1996;45(3-5):207-10.
[26] Massagu? J, Attisano L, Wrana JL. The TGF-beta family and its composite receptors. Trends Cell Biol. 1994;4(5):172-8.
[27] Barbara NP, Wrana JL, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem. 1999;274(2):584-94.
[28] Franz?n P, ten Dijke P, Ichijo H, Yamashita H, Schulz P, Heldin CH, Miyazono K. Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor. Cell. 1993;75(4):681-92.
[29] Lin HY, Wang XF, Ng-Eaton E, Weinberg RA, Lodish HF. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell. 1992;68(4):775-85.
[30] Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390(6659):465-71.
[31] Roberts A, Derynck R. Signaling schemes for TGF-b. A review of the meeting «The TGF-b Superfamily: Signaling and Development: FASEB Summer Res. Conf. Tucson, 2001:1-6.
[32] Souchelnytskyi S, ten Dijke P, Miyazono K, Heldin CH. Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses. EMBO J. 1996;15(22):6231-40.
[33] Wang T, Donahoe PK, Zervos AS. Specific interaction of type I receptors of the TGF-beta family with the immunophilin FKBP-12. Science. 1994;265(5172):674-6.
[34] Mathews LS, Vale WW. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 1991;65(6):973-82.
[35] Yamashita H, ten Dijke P, Franz?n P, Miyazono K, Heldin CH. Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta. J Biol Chem. 1994;269(31):20172-8.
[36] Brown CB, Boyer AS, Runyan RB, Barnett JV. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science. 1999;283(5410):2080-2.
[37] Datta PK, Chytil A, Gorska AE, Moses HL. Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling. J Biol Chem. 1998;273(52):34671-4.
[38] Choy L, Derynck R. The type II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response. J Biol Chem. 1998;273(47):31455-62.
[39] Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL. Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol. 2003;5(5):410-21.
[40] Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics. 1995;139(3):1347-58.
[41] Derynck R, Gelbart WM, Harland RM, Heldin CH, Kern SE, Massagu? J, Melton DA, Mlodzik M, Padgett RW, Roberts AB, Smith J, Thomsen GH, Vogelstein B, Wang XF. Nomenclature: vertebrate mediators of TGFbeta family signals. Cell. 1996;87(2):173.
[42] Itoh S, Itoh F, Goumans MJ, Ten Dijke P. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem. 2000;267(24):6954-67.
[43] Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J Cell Sci. 2001;114(Pt 24):4359-69.
[44] Attisano L, Lee-Hoeflich ST. The Smads. Genome Biol. 2001;2(8):REVIEWS3010.
[45] Zhang Y, Musci T, Derynck R. The tumor suppressor Smad4/DPC 4 as a central mediator of Smad function. Curr Biol. 1997;7(4):270-6.
[46] Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL, Falb D. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89(7):1165-73.
[47] Hata A, Lo RS, Wotton D, Lagna G, Massagu? J. Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Nature. 1997;388(6637):82-7.
[48] Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell. 2000;6(6):1365-75.
[49] Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell. 1998;95(6):779-91.
[50] Souchelnytskyi S, Tamaki K, Engstr?m U, Wernstedt C, ten Dijke P, Heldin CH. Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem. 1997;272(44):28107-15.
[51] Inman GJ, Nicol?s FJ, Hill CS. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell. 2002;10(2):283-94.
[52] Xu L, Kang Y, C?l S, Massagu? J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus. Mol Cell. 2002;10(2):271-82.
[53] Nakao A, Afrakhte M, Mor?n A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997;389(6651):631-5.
[54] It?h S, Landstr?m M, Hermansson A, Itoh F, Heldin CH, Heldin NE, ten Dijke P. Transforming growth factor beta1 induces nuclear export of inhibitory Smad7. J Biol Chem. 1998;273(44):29195-201.
[55] Datta PK, Moses HL. STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling. Mol Cell Biol. 2000;20(9):3157-67.
[56] Nagarajan RP, Zhang J, Li W, Chen Y. Regulation of Smad7 promoter by direct association with Smad3 and Smad4. J Biol Chem. 1999;274(47):33412-8.
[57] Gr?nroos E, Hellman U, Heldin CH, Ericsson J. Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell. 2002;10(3):483-93.
[58] Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature. 1999;400(6745):687-93.
[59] Heldin CH, ten Dijke P. SMAD destruction turns off signalling. Nat Cell Biol. 1999;1(8):E195-7.
[60] Alevizopoulos A, Mermod N. Transforming growth factor-beta: the breaking open of a black box. Bioessays. 1997;19(7):581-91.
[61] ten Dijke P, Miyazono K, Heldin CH. Signaling inputs converge on nuclear effectors in TGF-beta signaling. Trends Biochem Sci. 2000;25(2):64-70.
[62] Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 1998;17(11):3091-100.
[63] Shi Y, Wang YF, Jayaraman L, Yang H, Massagu? J, Pavletich NP. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell. 1998;94(5):585-94.
[64] Feng XH, Zhang Y, Wu RY, Derynck R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev. 1998;12(14):2153-63.
[65] Yahata T, de Caestecker MP, Lechleider RJ, Andriole S, Roberts AB, Isselbacher KJ, Shioda T. The MSG1 non-DNA-binding transactivator binds to the p300/CBP coactivators, enhancing their functional link to the Smad transcription factors. J Biol Chem. 2000;275(12):8825-34.
[66] Kim RH, Wang D, Tsang M, Martin J, Huff C, de Caestecker MP, Parks WT, Meng X, Lechleider RJ, Wang T, Roberts AB. A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Genes Dev. 2000;14(13):1605-16.
[67] Wotton D, Lo RS, Lee S, Massagu? J. A Smad transcriptional corepressor. Cell. 1999;97(1):29-39.
[68] Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q. The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev. 1999;13(17):2196-206.
[69] Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science. 1999;286(5440):771-4.
[70] Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature. 1997;389(6646):85-9.
[71] McCartney-Francis NL, Wahl SM. Transforming growth factor beta: a matter of life and death. J Leukoc Biol. 1994;55(3):401-9.
[72] Pietenpol JA, Stein RW, Moran E, Yaciuk P, Schlegel R, Lyons RM, Pittelkow MR, M?nger K, Howley PM, Moses HL. TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell. 1990;61(5):777-85.
[73] Barlat I, Henglein B, Plet A, Lamb N, Fernandez A, McKenzie F, Pouyss?gur J, Vi? A, Blanchard JM. TGF-beta 1 and cAMP attenuate cyclin A gene transcription via a cAMP responsive element through independent pathways. Oncogene. 1995;11(7):1309-18.
[74] Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371(6494):257-61.
[75] Datto MB, Yu Y, Wang XF. Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter. J Biol Chem. 1995;270(48):28623-8.
[76] Li L, Hu JS, Olson EN. Different members of the jun proto-oncogene family exhibit distinct patterns of expression in response to type beta transforming growth factor. J Biol Chem. 1990;265(3):1556-62.
[77] Bascom CC, Wolfshohl JR, Coffey RJ Jr, Madisen L, Webb NR, Purchio AR, Derynck R, Moses HL. Complex regulation of transforming growth factor beta 1, beta 2, and beta 3 mRNA expression in mouse fibroblasts and keratinocytes by transforming growth factors beta 1 and beta 2. Mol Cell Biol. 1989;9(12):5508-15.
[78] Zhang Y, Feng XH, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Nature. 1998;394(6696):909-13.
[79] Engel ME, McDonnell MA, Law BK, Moses HL. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem. 1999;274(52):37413-20.
[80] Peron P, Rahmani M, Zagar Y, Durand-Schneider AM, Lardeux B, Bernuau D. Potentiation of Smad transactivation by Jun proteins during a combined treatment with epidermal growth factor and transforming growth factor-beta in rat hepatocytes. role of phosphatidylinositol 3-kinase-induced AP-1 activation. J Biol Chem. 2001;276(13):10524-31.
[81] Yue J, Mulder KM. Requirement of Ras/MAPK pathway activation by transforming growth factor beta for transforming growth factor beta 1 production in a Smad-dependent pathway. J Biol Chem. 2000;275(40):30765-73.
[82] Reddy KB, Krueger JS, Kondapaka SB, Diglio CA. Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells. Int J Cancer. 1999;82(2):268-73.
[83] Kretzschmar M, Doody J, Timokhina I, Massagu? J. A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev. 1999;13(7):804-16.
[84] Lehmann K, Janda E, Pierreux CE, Ryt?maa M, Schulze A, McMahon M, Hill CS, Beug H, Downward J. Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev. 2000;14(20):2610-22.
[85] Labb? E, Letamendia A, Attisano L. Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Proc Natl Acad Sci U S A. 2000;97(15):8358-63.
[86] Mori N, Morishita M, Tsukazaki T, Giam CZ, Kumatori A, Tanaka Y, Yamamoto N. Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300. Blood. 2001;97(7):2137-44.
[87] Lee DK, Park SH, Yi Y, Choi SG, Lee C, Parks WT, Cho H, de Caestecker MP, Shaul Y, Roberts AB, Kim SJ. The hepatitis B virus encoded oncoprotein pX amplifies TGF-beta family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis. Genes Dev. 2001;15(4):455-66.
[88] Ulloa L, Doody J, Massagu? J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature. 1999;397(6721):710-3.
[89] Bitzer M, von Gersdorff G, Liang D, Dominguez-Rosales A, Beg AA, Rojkind M, B?ttinger EP. A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes Dev. 2000;14(2):187-97.
[90] Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958):577-84.
[91] Mulder KM. Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev. 2000;11(1-2):23-35.
[92] Sano Y, Harada J, Tashiro S, Gotoh-Mandeville R, Maekawa T, Ishii S. ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling. J Biol Chem. 1999;274(13):8949-57.
[93] Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001;12(1):27-36.
[94] Engel ME, Datta PK, Moses HL. RhoB is stabilized by transforming growth factor beta and antagonizes transcriptional activation. J Biol Chem. 1998;273(16):9921-6.
[95] Petritsch C, Beug H, Balmain A, Oft M. TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest. Genes Dev. 2000;14(24):3093-101.
[96] Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275(47):36803-10.