Regulation of TGF-β family signalling by ubiquitination and deubiquitination

Journal of Biochemistry

Volumn 154, Issue 6, 2013, Pages 481-489

  Imamura, Takeshi ^a,b,c,d   Oshima, Yusuke ^a,b,c,d   Hikita, Atsuhiko ^a,b,d  

^a EHIME UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b EHIME UNIVERSITY   (Japan)

^c EHIME UNIVERSITY HOSPITAL   (Japan)

^d JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

Author keywords

Deubiquitination; E3 ubiquitin ligases; TGF ubiquitination; Ubiquitin proteasome system

Indexed keywords

BONE MORPHOGENETIC PROTEIN; NUCLEIC ACID BINDING PROTEIN; PROTEIN ARKADIA; SMAD PROTEIN; SMAD UBIQUITIN REGULATORY FACTOR; TRANSFORMING GROWTH FACTOR BETA; UBIQUITIN; UBIQUITIN PROTEIN LIGASE E3; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; ARTICLE; CARBOXY TERMINAL SEQUENCE; DEUBIQUITINATION; ENZYME ACTIVITY; ENZYME STRUCTURE; ENZYME SUBSTRATE; HUMAN; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN MODIFICATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN STRUCTURE; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; UBIQUITINATION;

DEUBIQUITINATION; E3 UBIQUITIN LIGASES; TGF-ΒUBIQUITINATION; UBIQUITIN-PROTEASOME SYSTEM;

ANIMALS; HUMANS; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA; UBIQUITINATION;

EID: 84890534490     PISSN: 0021924X     EISSN: 17562651     Source Type: Journal    
DOI: 10.1093/jb/mvt097     Document Type: Article

References (87)

1. Siegel, P.M. and Massagué, J. (2003) Cytostatic and apoptotic actions of TGF-b in homeostasis and cancer. Nat. Rev. Cancer 3, 807-821
2. Heldin, C.H., Miyazono, K., and ten Dijke, P. (1997) TGF-b signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465-471
3. Derynck, R. and Zhang, Y.E. (2003) Smad-dependent and Smad-independent pathways in TGF-b family signalling. Nature 425, 577-584
4. ten Dijke, P. and Hill, C.S. (2004) New insights into TGF-b-Smad signaling. Trends Biochem. Sci. 29, 265-273
5. Massagué, J., Seoane, J., and Wotton, D. (2005) Smad transcription factors. Genes Dev. 19, 2783-2810
6. Miyazawa, K., Shinozaki, M., Hara, T., Furuya, T., and Miyazono, K. (2002) Two major Smad pathways in TGF-b superfamily signalling. Genes Cells 7, 1191-1204
7. Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y.Y., Grinnell, B.W., Richardson, M.A., Topper, J.N., Gimbrone, M.A. Jr., Wrana, J.L., and Falb, D. (1997) The MAD-related protein Smad7 associates with the TGFb receptor and functions as an antagonist of TGFb signaling. Cell 89, 1165-1173
8. Nakao, A., Imamura, T., Souchelnytskyi, S., Kawabata, M., Ishisaki, A., Oeda, E., Tamaki, K., Hanai, J., Heldin, C.H., Miyazono, K., and ten Dijke, P. (1997) TGF-b receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J. 16, 5353-5362
9. Imamura, T., Takase, M., Nishihara, A., Oeda, E., Hanai, J., Kawabata, M., and Miyazono, K. (1997) Smad6 inhibits signalling by the TGF-b superfamily. Nature 389, 622-626
10. Takase, M., Imamura, T., Sampath, T.K., Takeda, K., Ichijo, H., Miyazono, K., and Kawabata, M. (1998) Induction of Smad6 mRNA by bone morphogenetic proteins. Biochem. Biophys. Res. Commun. 244, 26-29
11. Hanyu, A., Ishidou, Y., Ebisawa, T., Shimanuki, T., Imamura, T., and Miyazono, K. (2001) The N domain of Smad7 is essential for specific inhibition of transforming growth factor-b signaling. J. Cell. Biol. 155, 1017-1027
12. Hata, A., Lagna, G., Massagué, J., and Hemmati- Brivanlou, A. (1998) Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 12, 186-197
13. Ishisaki, A., Yamato, K., Hashimoto, S., Nakao, A., Tamaki, K., Nonaka, K., ten Dijke, P., Sugino, H., and Nishihara, T. (1999) Differential inhibition of Smad6 and Smad7 on bone morphogenetic proteinand activin-mediated growth arrest and apoptosis in B cells. J. Biol. Chem. 274, 13637-13642
14. Mochizuki, T., Miyazaki, H., Hara, T., Furuya, T., Imamura, T., Watabe, T., and Miyazono, K. (2004) Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-b superfamily signaling. J. Biol. Chem. 279, 31568-31574
15. Hershko, A. and Ciechanover, A. (1998) The ubiquitin system. Annu. Rev. Biochem. 67, 425-479
16. Jesenberger, V. and Jentsch, S. (2002) Deadly encounter: Ubiquitin meets apoptosis. Nat. Rev. Mol. Cell. Biol. 3, 112-121
17. Laney, J.D. and Hochstrasser, M. (1999) Substrate targeting in the ubiquitin system. Cell 97, 427-430
18. Kimura, Y. and Tanaka, K. (2010) Regulatory mechanisms involved in the control of ubiquitin homeostasis. J. Biochem. 147, 793-798
19. Inoue, Y. and Imamura, T. (2008) Regulation of TGF-b family signaling by E3 ubiquitin ligases. Cancer Sci. 99, 2107-2112
20. Mukhopadhyay, D. and Riezman, H. (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315, 201-205
21. Tanno, H. and Komada, M. (2013) The ubiquitin code and its decoding machinery in the endocytic pathway. J. Biochem. 155, 497-504
22. Varshavsky, A. (2003) The N-end rule and regulation of apoptosis. Nat. Cell Biol. 5, 373-376
23. Ditzel, M., Wilson, R., Tenev, T., Zachariou, A., Paul, A., Deas, E., and Meier, P. (2003) Degradation of DIAP1 by the N-end rule pathway is essential for regulating apoptosis. Nat. Cell Biol. 5, 467-473
24. Zhu, H., Kavsak, P., Abdollah, S., Wrana, J.L., and Thomsen, G.H. (1999) A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687-693
25. Lin, X., Liang, M., and Feng, X.H. (2000) Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-b signaling. J. Biol. Chem. 275, 36818-36822
26. Zhang, Y., Chang, C., Gehling, D.J., Hemmati- Brivanlou, A., and Derynck, R. (2001) Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc. Natl Acad. Sci. USA 98, 974-979
27. Sapkota, G., Alarcon, C., Spagnoli, F.M., Brivanlou, A.H., and Massagué, J. (2007) Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol. Cell 25, 441-454
28. Nakano, A., Koinuma, D., Miyazawa, K., Uchida, T., Saitoh, M., Kawabata, M., Hanai, J., Akiyama, H., Abe, M., Miyazono, K., Matsumoto, T., and Imamura, T. (2009) Pin1 down-regulates transforming growth factorb (TGF-b) signaling by inducing degradation of Smad proteins. J. Biol. Chem. 284, 6109-6115
29. Kavsak, P., Rasmussen, R.K., Causing, C.G., Bonni, S., Zhu, H., Thomsen, G.H., and Warana, J.L. (2000) Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFb receptor for degradation. Mol. Cell 6, 1365-1375
30. Ebisawa, T., Fukuchi, M., Murakami, G., Chiba, T., Tanaka, K., Imamura, T., and Miyazono, K. (2001) Smurf1 interacts with transforming growth factor-b type I receptor through Smad7 and induces receptor degradation. J. Biol. Chem. 276, 12477-12480
31. Murakami, G., Watabe, T., Takaoka, K., Miyazono, K., and Imamura, T. (2003) Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol. Biol. Cell 14, 2809-2817
32. Tajima, Y., Goto, K., Yoshida, M., Shinomiya, K., Sekimoto, T., Yoneda, Y., Miyazono, K., and Imamura, T. (2003) Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-b signaling by Smad7. J. Biol. Chem. 278, 10716-10721
33. Suzuki, C., Murakami, G., Fukuchi, M., Shimanuki, T., Shikauchi, Y., Imamura, T., and Miyazono, K. (2002) Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J. Biol. Chem. 277, 39919-39925
34. Ogunjimi, A.A., Briant, D.J., Pece-Barbara, N., Le Roy, C., Di Guglielmo, G.M., Kavsak, P., Rasmussen, R.K., Seet, B.T., Sicheri, F., and Wrana, J.L. (2005) Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol. Cell 19, 297-308
35. Fukunaga, E., Inoue, Y., Komiya, S., Horiguchi, K., Goto, K., Saitoh, M., Miyazawa, K., Koinuma, D., Hanyu, A., and Imamura, T. (2008) Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells. J. Biol. Chem. 283, 35660-35667
36. Bonni, S., Wang, H.R., Causing, C.G., Kavsak, P., Stroschein, S.L., Luo, K., and Wrana, J.L. (2001) Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat. Cell Biol. 3, 587-595
37. Wiesner, S., Ogunjimi, A.A., Wang, H.R., Rotin, D., Sicheri, F., Wrana, J.L., and Forman-Kay, J.D. (2007) Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain. Cell 130, 651-662
38. Komuro, A., Imamura, T., Saitoh, M., Yoshida, Y., Yamori, T., Miyazono, K., and Miyazawa, K. (2004) Negative regulation of transforming growth factor-b (TGF-b) signaling by WW domain-containing protein 1 WWP1. Oncogene 23, 6914-6923
39. Kuratomi, G., Komuro, A., Goto, K., Shinozaki, M., Miyazawa, K., Miyazono, K., and Imamura, T. (2005) NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. J. Biochem. 386, 461-470
40. Morén, A., Imamura, T., Miyazono, K., Heldin, C.H., and Moustakas, A. (2005) Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J. Biol. Chem. 280, 22115-22123
41. Gao, S., Alarcó n, C., Sapkota, G., Rahman, S., Chen, P.Y., Goerner, N., Macias, M.J., Erdjument-Bromage, H., Tempst, P., and Massagué, J. (2009) Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGFbeta signaling. Mol. Cell 36, 457-468
42. Seo, S.R., Lallemand, F., Ferrand, N., Pessah, M., L'Hoste, S., Camonis, J., and Atfi, A. (2004) The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. EMBO J. 23, 3780-3792
43. Episkopou, V., Arkell, R., Timmons, P.M., Walsh, J.J., Andrew, R.L., and Swan, D. (2001) Induction of the mammalian node requires Arkadia function in the extraembryonic lineages. Nature 410, 825-830
44. Niederlander, C., Walsh, J.J., Episkopou, V., and Jones, C.M. (2001) Arkadia enhances nodal-related signaling to induce mesendoderm. Nature 410, 830-834
45. Koinuma, D., Shinozaki, M., Komuro, A., Goto, K., Saitoh, M., Hanyu, A., Ebina, M., Nukiwa, T., Miyazawa, K., Imamura, T., and Miyazono, K. (2003) Arkadia amplifies TGF-b superfamily signaling through degradation of Smad7. EMBO J. 22, 6458-6470
46. Nagano, Y., Mavrakis, K.J., Lee, K.L., Fujii, T., Koinuma, D., Sase, H., Yuki, K., Isogaya, K., Saitoh, M., Imamura, T., Episkopou, V., Miyazono, K., and Miyazawa, K. (2007) Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-b signaling. J. Biol. Chem. 282, 20492-20501
47. Le Scolan, E., Zhu, Q., Wang, L., Bandyopadhyay, A., Javelaud, D., Mauviel, A., Sun, L., and Luo, K. (2008) Transforming growth factor-b suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation. Cancer Res. 68, 3277-3328
48. Nagano, Y., Koinuma, D., Miyazawa, K., and Miyazono, K. (2010) Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells. J. Biochem. 147, 545-554
49. Liu, W., Rui, H., Wang, J., Lin, S., He, Y., Chen, M., Li, Q., Ye, Z., Zhang, S., Chan, S.C., Chen, Y.G., Han, J., and Lin, S.C. (2006) Axin is a scaffold protein in TGF-b signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 25, 1646-1658
50. Koinuma, D., Shinozaki, M., Nagano, Y., Ikushima, H., Horiguchi, K., Goto, K., Chano, T., Saitoh, M., Imamura, T., Miyazono, K., and Miyazawa, K. (2011) RB1CC1 protein positively regulates transforming growth factor-b signaling through the modulation of Arkadia E3 ubiquitin ligase activity. J. Biol. Chem. 286, 32502-32512
51. Xia, T., Lévy, L., Levillayer, F., Jia, B., Li, G., Neuveut, C., Buendia, M.A., Lan, K., and Wei, Y. (2013) The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor b (TGF-b) signaling by regulating ubiquitination of the E3 ligase Arkadia. J. Biol. Chem. 288, 1785-1794
52. Mizutani, A., Saitoh, M., Imamura, T., Miyazawa, K., and Miyazono, K. (2010) Arkadia complexes with clathrin adaptor AP2 and regulates EGF signalling. J. Biochem. 148, 733-741
53. Miyazono, K. and Koinuma, D. (2011) Arkadia-beyond the TGF-b pathway. J. Biochem. 149, 1-3
54. Poulsen, S.L., Hansen, R.K., Wagner, S.A., van Cuijk, L., van Belle, G.J., Streicher, W., Wikstro m, M., Choudhary, C., Houtsmuller, A.B., Marteijn, J.A., Bekker-Jensen, S., and Mailand, N. (2013) RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response. J. Cell. Biol. 201, 797-807
55. Erker, Y., Neyret-Kahn, H., Seeler, J.S., Dejean, A., Atfi, A., and Levy, L. (2013) Arkadia, a novel SUMOtargeted ubiquitin ligase involved in PML degradation. Mol. Cell. Biol. 33, 2163-2177
56. Ma, T., Chen, Y., Zhang, F., Yang, C.Y., Wang, S., and Yu, X. (2013) RNF111-dependent neddylation activates DNA damage-induced ubiquitination. Mol. Cell. 49, 897-907
57. Fukuchi, M., Imamura, T., Chiba, T., Ebisawa, T., Kawabata, M., Tanaka, K., and Miyazono, K. (2001) Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Mol. Biol. Cell 12, 1431-1443
58. Wan, M., Tang, Y., Tytler, E.M., Lu, C., Jin, B., Vickers, S.M., Yang, L., Shi, X., and Cao, X. (2004) Smad4 protein stability is regulated by ubiquitin ligase SCFb-TrCP1. J. Biol. Chem. 279, 14484-14487
59. Liang, M., Liang, Y.Y., Wrighton, K., Wrighton, K., Ungermannova, D., Wang, X.P., Brunicardi, F.C., Liu, X., Feng, X.H., and Lin, X. (2004) Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2. Mol. Cell. Biol. 24, 7524-7537
60. Xu, J. and Attisano, L. (2000) Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor b signaling by targeting Smads to the ubiquitin- proteasome pathway. Proc. Natl Acad. Sci. USA 97, 4820-4825
61. Nakayama, K.I. and Nakayama, K. (2006) Ubiquitin ligases: Cell-cycle control and cancer. Nat. Rev. Cancer 6, 369-381
62. Stroschein, S.L., Bonni, S., Wrana, J.L., and Luo, K. (2001) Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. Genes Dev. 15, 2822-2836
63. Wan, Y., Liu, X., and Kirschner, M.W. (2001) The anaphase- promoting complex mediates TGF-b signaling by targeting SnoN for destruction. Mol. Cell 8, 1027-1039
64. Stroschein, S.L., Wang, W., Zhou, S., Zhou, Q., and Luo, K. (1999) Negative feedback regulation of TGF-b signaling by the SnoN oncoprotein. Science 286, 771-774
65. Li, L., Xin, H., Xu, X., Huang, M., Zhang, X., Chen, Y., Zhang, S., Fu, X.Y., and Chang, Z. (2004) CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcription. Mol. Cell. Biol. 24, 856-864
66. Xin, H., Xu, X., Li, L., Ning, H., Rong, Y., Shang, Y., Wang, Y., Fu, X.Y., and Chang, Z. (2005) CHIP controls the sensitivity of transforming growth factor-b signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. J. Biol. Chem. 280, 20842-20850
67. Fang, D., Elly, C., Gao, B., Fang, N., Altman, Y., Joazeiro, C., Hunter, T., Copeland, N., Jenkins, N., and Liu, Y.C. (2002) Dysregulation of T lymphocyte function in itchy mice: A role for Itch in TH2 differentiation. Nat. Immunol. 3, 281-287
68. Perry, W.L., Hustad, C.M., Swing, D.A., O'Sullivan, T.N., Jenkins, N.A., and Copeland, N.G. (1998) The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat. Genet. 18, 143-146
69. Bai, Y., Yang, C., Hu, K., Elly, C., and Liu, Y.C. (2004) Itch E3 ligase-mediated regulation of TGF-b signaling by modulating Smad2 phosphorylation. Mol. Cell 15, 825-831
70. Lallemand, F., Seo, S.R., Ferrand, N., Pessah, M., L'Hoste, S., Rawadi, G., Roman-Roman, S., Camonis, J., and Atfi, A. (2005) AIP4 restricts transforming growth factor-b signaling through a ubiquitinationindependent mechanism. J. Biol. Chem. 280, 27645-27653
71. Dupont, S., Zacchigna, L., Cordenonsi, M., Soligo, S., Adorno, M., Rugge, M., and Piccolo, S. (2005) Germlayer specification and control of cell growth by ectodermin, a Smad4 ubiquitin ligase. Cell 121, 87-99
72. Dupont, S., Mamidi, A., Cordenonsi, M., Montagner, M., Zacchigna, L., Adorno, M., Martello, G., Stinchfield, M.J., Soligo, S., Morsut, L., Inui, M., Moro, S., Modena, N., Argenton, F., Newfeld, S.J., and Piccolo, S. (2009) FAM/USP9x, a deubiquitinating enzyme essential for TGFb signaling, controls Smad4 monoubiquitination. Cell 136, 123-135
73. Morsut, L., Yan, K.P., Enzo, E., Aragona, M., Soligo, S.M., Wendling, O., Mark, M., Khetchoumian, K., Bressan, G., Chambon, P., Dupont, S., Losson, R., and Piccolo, S. (2010) Negative control of Smad activity by ectodermin/Tif1g patterns the mammalian embryo. Development 137, 2571-2578
74. Agricola, E., Randall, R.A., Gaarenstroom, T., Dupont, S., and Hill, C.S. (2011) Recruitment of TIF1gamma to chromatin via its PHD fingerbromodomain activates its ubiquitin ligase and transcriptional repressor activities. Mol. Cell 43, 85-96
75. Sorrentino, A., Thakur, N., Grimsby, S., Marcusson, A., von Bulow, V., Schuster, N., Zhang, S., Heldin, C.H., and Landstro m, M. (2008) The type I TGF-b receptor engages TRAF6 to activate TAK1 in a receptor kinase independent manner. Nat. Cell Biol. 10, 1199-1207
76. Mu, Y., Sundar, R., Thakur, N., Ekman, M., Gudey, S.K., Yakymovych, M., Hermansson, A., Dimitriou, H., Bengoechea-Alonso, M.T., Ericsson, J., Heldin, C.H., and Landstro m, M. (2011) TRAF6 ubiquitinates TGFb type I receptor to promote its cleavage and nuclear translocation in cancer. Nat. Commun. 2, 330
77. Wicks, S.J., Haros, K., Maillard, M., Song, L., Cohen, R.E., Dijke, P.T., and Chantry, A. (2005) The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-b signalling. Oncogene 24, 8080-8084
78. Cutts, A.J., Soond, S.M., Powell, S., and Chantry, A. (2011) Early phase TGFb receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses. Int. J. Biochem. Cell Biol. 43, 604-612
79. Inui, M., Manfrin, A., Mamidi, A., Martello, G., Morsut, L., Soligo, S., Enzo, E., Moro, S., Polo, S., Dupont, S., Cordenonsi, M., and Piccolo, S. (2011) USP15 is a deubiquitylating enzyme for receptoractivated SMADs. Nat. Cell Biol. 13, 1368-1375
80. Eichhorn, P.J., Rodó n, L., Gonzà lez-Juncà, A., Dirac, A., Gili, M., Mart́nez-Sá ez, E., Aura, C., Barba, I., Peg, V., Prat, A., Cuartas, I., Jimenez, J., Garća- Dorado, D., Sahuquillo, J., Bernards, R., Baselga, J., and Seoane, J. (2012) USP15 stabilizes TGF-b receptor I and promotes oncogenesis through the activation of TGF-b signaling in glioblastoma. Nat. Med. 18, 429-435
81. Zhao, Y., Thornton, A.M., Kinney, M.C., Ma, C.A., Spinner, J.J., Fuss, I.J., Shevach, E.M., and Jain, A. (2011) The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor b (TGF-b) signaling and the development of regulatory T cells. J. Biol. Chem. 286, 40520-40530
82. Tanaka, N., Kaneko, K., Asao, H., Kasai, H., Endo, Y., Fujita, T., Takeshita, T., and Sugamura, K. (1999) Possible involvement of a novel STAMassociated molecule ''AMSH'' in intracellular signal transduction mediated by cytokines. J. Biol. Chem. 274, 19129-19135
83. Itoh, F., Asao, H., Sugamura, K., Heldin, C.H., ten Dijke, P., and Itoh, S. (2001) Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J. 20, 4132-4142
84. Ibarrola, N., Kratchmarova, I., Nakajima, D., Schiemann, W.P., Moustakas, A., Pandey, A., and Mann, M. (2004) Cloning of a novel signaling molecule, AMSH-2, that potentiates transforming growth factor b signaling. BMC Cell Biol. 5, 2
85. Ozdamar, B., Bose, R., Barrios-Rodiles, M., Wang, H.R., Zhang, Y., and Wrana, J.L. (2005) Regulation of the polarity protein Par6 by TGF-b receptors controls epithelial cell plasticity. Science 307, 1603-1609
86. Kiyono, K., Suzuki, H.I., Matsuyama, H., Morishita, Y., Komuro, A., Kano, M.R., Sugimoto, K., and Miyazono, K. (2009) Autophagy is activated by TGF-b and potentiates TGF-b-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res. 69, 8844-8852
87. Suzuki, H.I., Kiyono, K., and Miyazono, K. (2010) Regulation of autophagy by transforming growth factor-b (TGF-b) signaling. Autophagy 6, 645-647