Role of Smads in TGFβ signaling (original) (raw)

References

• Abdollah S, Macías-Silva M, Tsukazaki T, Hayashi H, Attisano L, Wrana JL (1997) TβRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J Biol Chem 272:27678–27685
  PubMed CAS Google Scholar
• Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, Solari A, Bobisse S, Rondina MB, Guzzardo V et al (2009) A Mutant-p53/Smad complex opposes p63 to empower TGFβ-induced metastasis. Cell 137:87–98
  PubMed CAS Google Scholar
• Akiyoshi S, Inoue H, Hanai J, Kusanagi K, Nemoto N, Miyazono K, Kawabata M (1999) c-Ski acts as a transcriptional co-repressor in transforming growth factor-β signaling through interaction with Smads. J Biol Chem 274:35269–35277
  PubMed CAS Google Scholar
• Alarcón C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ et al (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell 139:757–769
  PubMed Google Scholar
• Alcorn JF, Guala AS, Velden J van der, McElhinney B, Irvin CG, Davis RJ, Janssen-Heininger YM (2008) Jun N-terminal kinase 1 regulates epithelial-to-mesenchymal transition induced by TGF-β1. J Cell Sci 121:1036–1045
  PubMed CAS Google Scholar
• Araki S, Eitel JA, Batuello CN, Bijangi-Vishehsaraei K, Xie XJ, Danielpour D, Pollok KE, Boothman DA, Mayo LD (2010) TGF-β1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer. J Clin Invest 120:290–302
  PubMed CAS Google Scholar
• Azar R, Alard A, Susini C, Bousquet C, Pyronnet S (2009) 4E-BP1 is a target of Smad4 essential for TGFβ-mediated inhibition of cell proliferation. EMBO J 28:3514–3522
  PubMed CAS Google Scholar
• Benus GF, Wierenga AT, Gorter DJ de, Schuringa JJ, Bennekum AM van, Drenth-Diephuis L, Vellenga E, Eggen BJ (2005) Inhibition of the transforming growth factor β (TGFβ) pathway by interleukin-1β is mediated through TGFβ-activated kinase 1 phosphorylation of SMAD3. Mol Biol Cell 16:3501–3510
  PubMed CAS Google Scholar
• Berx G, Raspe E, Christofori G, Thiery JP, Sleeman JP (2007) Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin Exp Metastasis 24:587–597
  PubMed CAS Google Scholar
• Bian Y, Terse A, Du J, Hall B, Molinolo A, Zhang P, Chen W, Flanders KC, Gutkind JS, Wakefield LM et al (2009) Progressive tumor formation in mice with conditional deletion of TGF-β signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway. Cancer Res 69:5918–5926
  PubMed CAS Google Scholar
• Bierie B, Moses HL (2006) TGF-β and cancer. Cytokine Growth Factor Rev 17:29–40
  PubMed CAS Google Scholar
• Brandl M, Seidler B, Haller F, Adamski J, Schmid RM, Saur D, Schneider G (2010) IKKα controls canonical TGFβ-SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in panc1 cells. J Cell Sci 123:4231–4239
  PubMed CAS Google Scholar
• Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9:582–589
  PubMed CAS Google Scholar
• Caestecker MP de, Parks WT, Frank CJ, Castagnino P, Bottaro DP, Roberts AB, Lechleider RJ (1998) Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev 12:1587–1592
  PubMed Google Scholar
• Chacko BM, Qin BY, Tiwari A, Shi G, Lam S, Hayward LJ, De Caestecker M, Lin K (2004) Structural basis of heteromeric smad protein assembly in TGF-β signaling. Mol Cell 15:813–823
  PubMed CAS Google Scholar
• Chang CC, Lin DY, Fang HI, Chen RH, Shih HM (2005) Daxx mediates the small ubiquitin-like modifier-dependent transcriptional repression of Smad4. J Biol Chem 280:10164–10173
  PubMed CAS Google Scholar
• Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH (2010) TGF-β-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol 12:286–293
  PubMed CAS Google Scholar
• Daly AC, Randall RA, Hill CS (2008) Transforming growth factor β-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol Cell Biol 28:6889–6902
  PubMed CAS Google Scholar
• Daly AC, Vizan P, Hill CS (2010) Smad3 protein levels are modulated by Ras activity and during the cell cycle to dictate transforming growth factor-β responses. J Biol Chem 285:6489–6497
  PubMed CAS Google Scholar
• Davis BN, Hilyard AC, Lagna G, Hata A (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454:56–61
  PubMed CAS Google Scholar
• Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A (2010) Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell 39:373–384
  PubMed CAS Google Scholar
• Descargues P, Sil AK, Sano Y, Korchynskyi O, Han G, Owens P, Wang X-J, Karin M (2008) IKKα is a critical coregulator of a Smad4 independent TGFβ-Smad2/3 signaling pathway that controls keratinocyte differentiation. Proc Natl Acad Sci USA 105:2487–2492
  PubMed CAS Google Scholar
• Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL (2003) Distinct endocytic pathways regulate TGF-β receptor signalling and turnover. Nat Cell Biol 5:410–421
  PubMed Google Scholar
• Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J, Perry SR, Labrot ES, Wu X, Lis R et al (2011) SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470:269–273
  PubMed CAS Google Scholar
• Dong C, Li Z, Alvarez R Jr, Feng X-H, Goldschmidt-Clermont PJ (2000) Microtubule binding to Smads may regulate TGFβ activity. Mol Cell 5:27–34
  PubMed CAS Google Scholar
• Dupont S, Zacchigna L, Cordenonsi M, Soligo S, Adorno M, Rugge M, Piccolo S (2005) Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell 121:87–99
  PubMed CAS Google Scholar
• Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, Martello G, Stinchfield MJ, Soligo S, Morsut L et al (2009) FAM/USP9x, a deubiquitinating enzyme essential for TGFβ signaling, controls Smad4 monoubiquitination. Cell 136:123–135
  PubMed CAS Google Scholar
• Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K (2001) Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276:12477–12480
  PubMed CAS Google Scholar
• Erickson RA, Liu X (2009) Association of v-ErbA with Smad4 disrupts TGF-β signaling. Mol Biol Cell 20:1509–1519
  PubMed CAS Google Scholar
• Feng X-H, Derynck R (1997) A kinase subdomain of transforming growth factor-β (TGF-β) type I receptor determines the TGF-β intracellular signaling specificity. EMBO J 16:3912–3923
  PubMed CAS Google Scholar
• Feng XH, Liang YY, Liang M, Zhai W, Lin X (2002) Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-β-mediated induction of the CDK inhibitor p15(Ink4B). Mol Cell 9:133–143
  PubMed CAS Google Scholar
• Ferrand N, Atfi A, Prunier C (2010) The oncoprotein c-ski functions as a direct antagonist of the transforming growth factor-β type I receptor. Cancer Res 70:8457–8466
  PubMed CAS Google Scholar
• Fuentealba LC, Eivers E, Ikeda A, Hurtado C, Kuroda H, Pera EM, De Robertis EM (2007) Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131:980–993
  PubMed CAS Google Scholar
• Fukuchi M, Imamura T, Chiba T, Ebisawa T, Kawabata M, Tanaka K, Miyazono K (2001) Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Mol Biol Cell 12:1431–1443
  PubMed CAS Google Scholar
• Gao S, Alarcon C, Sapkota G, Rahman S, Chen PY, Goerner N, Macias MJ, Erdjument-Bromage H, Tempst P, Massague J (2009) Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling. Mol Cell 36:457–468
  PubMed CAS Google Scholar
• Giampieri S, Manning C, Hooper S, Jones L, Hill CS, Sahai E (2009) Localized and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 11:1287–1296
  PubMed CAS Google Scholar
• Goumans M-J, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, Dijke P ten (2003) Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol Cell 12:817–828
  PubMed CAS Google Scholar
• Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Farshid G, Lim YY et al (2011) An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell 22:1686–1698
  Google Scholar
• Grönroos E, Hellman U, Heldin C-H, Ericsson J (2002) Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell 10:483–493
  PubMed Google Scholar
• Guo X, Waddell DS, Wang W, Wang Z, Liberati NT, Yong S, Liu X, Wang XF (2008) Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-β signaling. Oncogene 27:7235–7247
  PubMed CAS Google Scholar
• Hahn SA, Schutte M, Hoque ATMS, Moskaluk CA, Costa LT da, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH et al (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350–353
  PubMed CAS Google Scholar
• Halder SK, Rachakonda G, Deane NG, Datta PK (2008) Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer 99:957–965
  PubMed CAS Google Scholar
• Hannigan A, Smith P, Kalna G, Lo Nigro C, Orange C, O'Brien DI, Shah R, Syed N, Spender LC, Herrera B et al (2010) Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter. J Clin Invest 120:2842–2857
  PubMed CAS Google Scholar
• Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MAJ, Wrana JL et al (1997) The MAD-related protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89:1165–1173
  PubMed CAS Google Scholar
• Hayes S, Chawla A, Corvera S (2002) TGF β receptor internalization into EEA1-enriched early endosomes: role in signaling to Smad2. J Cell Biol 158:1239–1249
  PubMed CAS Google Scholar
• He W, Dorn DC, Erdjument-Bromage H, Tempst P, Moore MA, Massagué J (2006) Hematopoiesis controlled by distinct TIF1γ and Smad4 branches of the TGFβ pathway. Cell 125:929–941
  PubMed CAS Google Scholar
• Heikkinen PT, Nummela M, Jokilehto T, Grenman R, Kähäri VM, Jaakkola PM (2010a) Hypoxic conversion of SMAD7 function from an inhibitor into a promoter of cell invasion. Cancer Res 70:5984–5993
  PubMed CAS Google Scholar
• Heikkinen PT, Nummela M, Leivonen SK, Westermarck J, Hill CS, Kahari VM, Jaakkola PM (2010b) Hypoxia-activated Smad3-specific dephosphorylation by PP2A. J Biol Chem 285:3740–3749
  PubMed CAS Google Scholar
• Heldin C-H, Landström M, Moustakas A (2009) Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol 21:166–176
  PubMed CAS Google Scholar
• Ho J, Cocolakis E, Dumas VM, Posner BI, Laporte SA, Lebrun JJ (2005) The G protein-coupled receptor kinase-2 is a TGFβ-inducible antagonist of TGFβ signal transduction. EMBO J 24:3247–3258
  PubMed CAS Google Scholar
• Hoot KE, Lighthall J, Han G, Lu SL, Li A, Ju W, Kulesz-Martin M, Bottinger E, Wang XJ (2008) Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. J Clin Invest 118:2722–2732
  PubMed CAS Google Scholar
• Horiguchi K, Shirakihara T, Nakano A, Imamura T, Miyazono K, Saitoh M (2009) Role of Ras signaling in the induction of snail by transforming growth factor-β. J Biol Chem 284:245–253
  PubMed CAS Google Scholar
• Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17:548–558
  PubMed CAS Google Scholar
• Huminiecki L, Goldovsky L, Freilich S, Moustakas A, Ouzounis CA, Heldin C-H (2009) Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom. BMC Evol Biol 9:28
  PubMed Google Scholar
• Ikushima H, Miyazono K (2010) TGFβ signalling: a complex web in cancer progression. Nat Rev Cancer 10:415–424
  PubMed CAS Google Scholar
• Ito I, Hanyu A, Wayama M, Goto N, Katsuno Y, Kawasaki S, Nakajima Y, Kajiro M, Komatsu Y, Fujimura A et al (2010) Estrogen inhibits transforming growth factor β signaling by promoting Smad2/3 degradation. J Biol Chem 285:14747–14755
  PubMed CAS Google Scholar
• Itoh S, Landström M, Hermansson A, Itoh F, Heldin C-H, Heldin N-E, Dijke P ten (1998) Transforming growth factor β1 induces nuclear export of inhibitory Smad7. J Biol Chem 273:29195–29201
  PubMed CAS Google Scholar
• Jayaraman L, Massagué J (2000) Distinct oligomeric states of SMAD proteins in the transforming growth factor-β pathway. J Biol Chem 275:40710–40717
  PubMed CAS Google Scholar
• Ju W, Ogawa A, Heyer J, Nierhof D, Yu L, Kucherlapati R, Shafritz DA, Böttinger EP (2006) Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol Cell Biol 26:654–667
  PubMed CAS Google Scholar
• Kamaraju AK, Roberts AB (2005) Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-β-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo. J Biol Chem 280:1024–1036
  PubMed CAS Google Scholar
• Kamiya Y, Miyazono K, Miyazawa K (2010) Smad7 inhibits transforming growth factor-β family type I receptors through two distinct modes of interaction. J Biol Chem 285:30804–30813
  PubMed CAS Google Scholar
• Kang JS, Liu C, Derynck R (2009) New regulatory mechanisms of TGF-β receptor function. Trends Cell Biol 19:385–394
  PubMed CAS Google Scholar
• Kawabata M, Inoue H, Hanyu A, Imamura T, Miyazono K (1998) Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors. EMBO J 17:4056–4065
  PubMed CAS Google Scholar
• Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL (2000) Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol Cell 6:1365–1375
  PubMed CAS Google Scholar
• Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, Brumwell AN, Wheeler SE, Kreidberg JA et al (2009a) Epithelial cell α3β1 integrin links β-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest 119:213–224
  PubMed CAS Google Scholar
• Kim Y, Kugler MC, Wei Y, Kim KK, Li X, Brumwell AN, Chapman HA (2009b) Integrin α3β1-dependent β-catenin phosphorylation links epithelial Smad signaling to cell contacts. J Cell Biol 184:309–322
  PubMed CAS Google Scholar
• Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, Ebina M, Nukiwa T, Miyazawa K, Imamura T et al (2003) Arkadia amplifies TGF-β superfamily signalling through degradation of Smad7. EMBO J 22:6458–6470
  PubMed CAS Google Scholar
• Koinuma D, Tsutsumi S, Kamimura N, Taniguchi H, Miyazawa K, Sunamura M, Imamura T, Miyazono K, Aburatani H (2009) Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor beta signaling. Mol Cell Biol 29:172–186
  PubMed CAS Google Scholar
• Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, Miyazawa K (2004) Negative regulation of transforming growth factor-β (TGF-β) signaling by WW domain-containing protein 1 (WWP1). Oncogene 23:6914–6923
  PubMed CAS Google Scholar
• Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, Cheng JQ (2008) MicroRNA-155 is regulated by the transforming growth factor β/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 28:6773–6784
  PubMed CAS Google Scholar
• Korpal M, Lee ES, Hu G, Kang Y (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283:14910–14914
  PubMed CAS Google Scholar
• Korpal M, Yan J, Lu X, Xu S, Lerit DA, Kang Y (2009) Imaging transforming growth factor-β signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med 15:960–966
  PubMed CAS Google Scholar
• Kowanetz M, Lönn P, Vanlandewijck M, Kowanetz K, Heldin C-H, Moustakas A (2008) TGFβ induces SIK to negatively regulate type I receptor kinase signaling. J Cell Biol 182:655–662
  PubMed CAS Google Scholar
• Kretzschmar M, Doody J, Timokhina I, Massagué J (1999) A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras. Genes Dev 13:804–816
  PubMed CAS Google Scholar
• Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K, Imamura T (2005) NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4–2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor. Biochem J 386:461–470
  PubMed CAS Google Scholar
• Kurisaki A, Kose S, Yoneda Y, Heldin C-H, Moustakas A (2001) Transforming growth factor-β induces nuclear import of Smad3 in an importin-β1 and Ran-dependent manner. Mol Biol Cell 12:1079–1091
  PubMed CAS Google Scholar
• Kurisaki A, Kurisaki K, Kowanetz M, Sugino H, Yoneda Y, Heldin C-H, Moustakas A (2006) The mechanism of nuclear export of Smad3 involves exportin 4 and Ran. Mol Cell Biol 26:1318–1332
  PubMed CAS Google Scholar
• Le Scolan E, Zhu Q, Wang L, Bandyopadhyay A, Javelaud D, Mauviel A, Sun L, Luo K (2008) Transforming growth factor-β suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation. Cancer Res 68:3277–3285
  PubMed Google Scholar
• Lecanda J, Ganapathy V, D'Aquino-Ardalan C, Evans B, Cadacio C, Ayala A, Gold LI (2009) TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest. Cell Cycle 8:742–756
  PubMed CAS Google Scholar
• Lee B-H, Chen W, Stippec S, Cobb MH (2007) Biological cross-talk between WNK1 and the transforming growth factor β-Smad signaling pathway. J Biol Chem 282:17985–17996
  PubMed CAS Google Scholar
• Lee PS, Chang C, Liu D, Derynck R (2003) Sumoylation of Smad4, the common Smad mediator of transforming growth factor-β family signaling. J Biol Chem 278:27853–27863
  PubMed CAS Google Scholar
• Levy L, Howell M, Das D, Harkin S, Episkopou V, Hill CS (2007) Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Mol Cell Biol 27:6068–6083
  PubMed CAS Google Scholar
• Liang M, Liang YY, Wrighton K, Ungermannova D, Wang XP, Brunicardi FC, Liu X, Feng XH, Lin X (2004) Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2. Mol Cell Biol 24:7524–7537
  PubMed CAS Google Scholar
• Lin X, Liang M, Feng XH (2000) Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-β signaling. J Biol Chem 275:36818–36822
  PubMed CAS Google Scholar
• Lin X, Liang M, Liang YY, Brunicardi FC, Feng XH (2003) SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4. J Biol Chem 278:31043–31048
  PubMed CAS Google Scholar
• Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC et al (2006) PPM1A functions as a Smad phosphatase to terminate TGFβ signaling. Cell 125:915–928
  PubMed CAS Google Scholar
• Liu IM, Schilling SH, Knouse KA, Choy L, Derynck R, Wang XF (2009) TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. EMBO J 28:88–98
  PubMed CAS Google Scholar
• Liu W, Rui H, Wang J, Lin S, He Y, Chen M, Li Q, Ye Z, Zhang S, Chan SC et al (2006) Axin is a scaffold protein in TGF-β signaling that promotes degradation of Smad7 by Arkadia. EMBO J 25:1646–1658
  PubMed CAS Google Scholar
• Lo RS, Chen YG, Shi Y, Pavletich NP, Massagué J (1998) The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-β receptors. EMBO J 17:996–1005
  PubMed CAS Google Scholar
• Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q (1999) The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling. Genes Dev 13:2196–2206
  PubMed CAS Google Scholar
• Lönn P, Heide L van der, Dahl M, Hellman U, Heldin C-H, Moustakas A (2010) PARP-1 attenuates Smad-mediated transcription. Mol Cell 40:521–532
  PubMed Google Scholar
• Massagué J (2004) G1 cell-cycle control and cancer. Nature 432:298–306
  PubMed Google Scholar
• Massagué J (2008) TGFβ in cancer. Cell 134:215–230
  PubMed Google Scholar
• Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F (2004) Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430:226–231
  PubMed CAS Google Scholar
• Matsuura I, Chiang KN, Lai CY, He D, Wang G, Ramkumar R, Uchida T, Ryo A, Lu K, Liu F (2010) Pin1 promotes transforming growth factor-β-induced migration and invasion. J Biol Chem 285:1754–1764
  PubMed CAS Google Scholar
• Mavrakis KJ, Andrew RL, Lee KL, Petropoulou C, Dixon JE, Navaratnam N, Norris DP, Episkopou V (2007) Arkadia enhances Nodal/TGF-β signaling by coupling phospho-Smad2/3 activity and turnover. PLoS Biol 5:e67
  PubMed Google Scholar
• Millet C, Yamashita M, Heller M, Yu LR, Veenstra TD, Zhang YE (2009) A negative feedback control of transforming growth factor-β signaling by glycogen synthase kinase 3-mediated Smad3 linker phosphorylation at Ser-204. J Biol Chem 284:19808–19816
  PubMed CAS Google Scholar
• Miyake T, Alli NS, McDermott JC (2010) Nuclear function of Smad7 promotes myogenesis. Mol Cell Biol 30:722–735
  PubMed CAS Google Scholar
• Morén A, Hellman U, Inada Y, Imamura T, Heldin C-H, Moustakas A (2003) Differential ubiquitination defines the functional status of the tumor suppressor Smad4. J Biol Chem 278:33571–33582
  PubMed Google Scholar
• Morén A, Raja E, Heldin C-H, Moustakas A (2011) Negative regulation of TGFβ signaling by the kinase LKB1 and the scaffolding protein LIP1. J Biol Chem 286:341–353
  PubMed Google Scholar
• Mori S, Matsuzaki K, Yoshida K, Furukawa F, Tahashi Y, Yamagata H, Sekimoto G, Seki T, Matsui H, Nishizawa M et al (2004) TGF-β and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene 23:7416–7429
  PubMed CAS Google Scholar
• Moustakas A, Heldin C-H (2005) Non-Smad TGF-β signals. J Cell Sci 118:3573–3584
  PubMed CAS Google Scholar
• Moustakas A, Heldin C-H (2007) Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 98:1512–1520
  PubMed CAS Google Scholar
• Moustakas A, Heldin C-H (2009) The regulation of TGFβ signal transduction. Development 136:3699–3714
  PubMed CAS Google Scholar
• Nagano Y, Mavrakis KJ, Lee KL, Fujii T, Koinuma D, Sase H, Yuki K, Isogaya K, Saitoh M, Imamura T et al (2007) Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-β signaling. J Biol Chem 282:20492–20501
  PubMed CAS Google Scholar
• Nakahata S, Yamazaki S, Nakauchi H, Morishita K (2010) Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma. Oncogene 29:4157–4169
  PubMed CAS Google Scholar
• Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M, Hanai J, Akiyama H, Abe M, Miyazono K et al (2009) Pin1 down-regulates transforming growth factor-β (TGF-β) signaling by inducing degradation of Smad proteins. J Biol Chem 284:6109–6115
  PubMed CAS Google Scholar
• Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin N-E, Heldin C-H et al (1997) Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389:631–635
  PubMed CAS Google Scholar
• Niimi H, Pardali K, Vanlandewijck M, Heldin C-H, Moustakas A (2007) Notch signaling is necessary for epithelial growth arrest by TGF-β. J Cell Biol 176:695–707
  PubMed CAS Google Scholar
• Ohshima T, Shimotohno K (2003) Transforming growth factor-β-mediated signaling via the p38 MAP kinase pathway activates Smad-dependent transcription through SUMO-1 modification of Smad4. J Biol Chem 278:50833–50842
  PubMed CAS Google Scholar
• Papageorgis P, Lambert AW, Ozturk S, Gao F, Pan H, Manne U, Alekseyev YO, Thiagalingam A, Abdolmaleky HM, Lenburg M et al (2010) Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res 70:968–978
  PubMed CAS Google Scholar
• Pardali E, Goumans MJ, Dijke P ten (2010) Signaling by members of the TGF-β family in vascular morphogenesis and disease. Trends Cell Biol 20:556–567
  PubMed CAS Google Scholar
• Peinado H, Quintanilla M, Cano A (2003) Transforming growth factor β-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 278:21113–21123
  PubMed CAS Google Scholar
• Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428
  PubMed CAS Google Scholar
• Penheiter SG, Mitchell H, Garamszegi N, Edens M, Dore JJ Jr, Leof EB (2002) Internalization-dependent and -independent requirements for transforming growth factor β receptor signaling via the Smad pathway. Mol Cell Biol 22:4750–4759
  PubMed CAS Google Scholar
• Petersen M, Pardali E, Horst G van der, Cheung H, Hoogen C van den, Pluijm G van der, Dijke P ten (2010) Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene 29:1351–1361
  PubMed CAS Google Scholar
• Pierreux CE, Nicolas FJ, Hill CS (2000) Transforming growth factor β-independent shuttling of Smad4 between the cytoplasm and nucleus. Mol Cell Biol 20:9041–9054
  PubMed CAS Google Scholar
• Pulaski L, Landström M, Heldin C-H, Souchelnytskyi S (2001) Phosphorylation of Smad7 at Ser-249 does not interfere with its inhibitory role in transforming growth factor-β-dependent signaling but affects Smad7-dependent transcriptional activation. J Biol Chem 276:14344–14349
  PubMed CAS Google Scholar
• Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 100:8621–8623
  PubMed CAS Google Scholar
• Roelen BA, Cohen OS, Raychowdhury MK, Chadee DN, Zhang Y, Kyriakis JM, Alessandrini AA, Lin HY (2003) Phosphorylation of threonine 276 in Smad4 is involved in transforming growth factor-β-induced nuclear accumulation. Am J Physiol Cell Physiol 285:C823–C830
  PubMed CAS Google Scholar
• Ross S, Hill CS (2008) How the Smads regulate transcription. Int J Biochem Cell Biol 40:383–408
  PubMed CAS Google Scholar
• Runyan CE, Hayashida T, Hubchak S, Curley JF, Schnaper HW (2009) Role of SARA (SMAD anchor for receptor activation) in maintenance of epithelial cell phenotype. J Biol Chem 284:25181–25189
  PubMed CAS Google Scholar
• Sapkota G, Alarcón C, Spagnoli FM, Brivanlou AH, Massagué J (2007) Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol Cell 25:441–454
  PubMed CAS Google Scholar
• Schmierer B, Tournier AL, Bates PA, Hill CS (2008) Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system. Proc Natl Acad Sci USA 105:6608–6613
  PubMed CAS Google Scholar
• Seo SR, Lallemand F, Ferrand N, Pessah M, L'Hoste S, Camonis J, Atfi A (2004) The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. EMBO J 23:3780–3792
  PubMed CAS Google Scholar
• Seoane J, Pouponnot C, Staller P, Schader M, Eilers M, Massagué J (2001) TGFβ influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol 3:400–408
  PubMed CAS Google Scholar
• Seong H-A, Jung H, Ha H (2010) Murine protein serine/threonine kinase 38 stimulates TGF-β signaling in a kinase-dependent manner via direct phosphorylation of Smad proteins. J Biol Chem 285:30959–30970
  PubMed CAS Google Scholar
• Shan B, Yao TP, Nguyen HT, Zhuo Y, Levy DR, Klingsberg RC, Tao H, Palmer ML, Holder KN, Lasky JA (2008) Requirement of HDAC6 for transforming growth factor-β1-induced epithelial-mesenchymal transition. J Biol Chem 283:21065–21073
  PubMed CAS Google Scholar
• Shi W, Sun C, He B, Xiong W, Shi X, Yao D, Cao X (2004) GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol 164:291–300
  PubMed CAS Google Scholar
• Shi Y, Massagué J (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685–700
  PubMed CAS Google Scholar
• Shi Y, Wang YF, Jayaraman L, Yang HJ, Massagué J, Pavletich NP (1998) Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-β signaling. Cell 94:585–594
  PubMed CAS Google Scholar
• Shirakihara T, Horiguchi K, Miyazawa K, Ehata S, Shibata T, Morita I, Miyazono K, Saitoh M (2011) TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J 30:783–795
  PubMed CAS Google Scholar
• Shukla A, Malik M, Cataisson C, Ho Y, Friesen T, Suh KS, Yuspa SH (2009) TGF-β signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3. Nat Cell Biol 11:777–784
  PubMed CAS Google Scholar
• Simonsson M, Heldin C-H, Ericsson J, Grönroos E (2005) The balance between acetylation and deacetylation controls Smad7 stability. J Biol Chem 280:21797–21803
  PubMed CAS Google Scholar
• Simonsson M, Kanduri M, Grönroos E, Heldin C-H, Ericsson J (2006) The DNA binding activities of Smad2 and Smad3 are regulated by coactivator-mediated acetylation. J Biol Chem 281:39870–39880
  PubMed CAS Google Scholar
• Singh G, Singh SK, Konig A, Reutlinger K, Nye MD, Adhikary T, Eilers M, Gress TM, Fernandez-Zapico ME, Ellenrieder V (2010) Sequential activation of NFAT and c-Myc transcription factors mediates the TGF-β switch from a suppressor to a promoter of cancer cell proliferation. J Biol Chem 285:27241–27250
  PubMed CAS Google Scholar
• Smith AP, Verrecchia A, Faga G, Doni M, Perna D, Martinato F, Guccione E, Amati B (2009) A positive role for Myc in TGFβ-induced Snail transcription and epithelial-to-mesenchymal transition. Oncogene 28:422–430
  PubMed CAS Google Scholar
• Soond SM, Chantry A (2011) Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT. Oncogene (in press)
• Souchelnytskyi S, Tamaki K, Engström U, Wernstedt C, Dijke P ten, Heldin C-H (1997) Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-β signaling. J Biol Chem 272:28107–28115
  PubMed CAS Google Scholar
• Stroschein SL, Wang W, Zhou SL, Zhou Q, Luo KX (1999) Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 286:771–774
  PubMed CAS Google Scholar
• Tajima Y, Goto K, Yoshida M, Shinomiya K, Sekimoto T, Yoneda Y, Miyazono K, 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-β signaling by Smad7. J Biol Chem 278:10716–10721
  PubMed CAS Google Scholar
• Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890
  PubMed CAS Google Scholar
• Thuault S, Tan E-J, Peinado H, Cano A, Heldin C-H, Moustakas A (2008) HMGA2 and Smads coregulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem 283:33437–33446
  PubMed CAS Google Scholar
• Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFβ receptor. Cell 95:779–791
  PubMed CAS Google Scholar
• Tu AW, Luo K (2007) Acetylation of Smad2 by the co-activator p300 regulates activin and transforming growth factor β response. J Biol Chem 282:21187–21196
  PubMed CAS Google Scholar
• Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW, Wrana JL (2008) TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10:837–848
  PubMed CAS Google Scholar
• Vijayachandra K, Higgins W, Lee J, Glick A (2009) Induction of p16ink4a and p19ARF by TGFβ1 contributes to growth arrest and senescence response in mouse keratinocytes. Mol Carcinog 48:181–186
  PubMed CAS Google Scholar
• Vincent T, Neve EPA, Johnson JR, Kukalev A, Rojo F, Albanell J, Pietras K, Virtanen I, Philipson L, Leopold PL et al (2009) A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. Nat Cell Biol 11:943–950
  PubMed CAS Google Scholar
• Waerner T, Alacakaptan M, Tamir I, Oberauer R, Gal A, Brabletz T, Schreiber M, Jechlinger M, Beug H (2006) ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10:227–239
  PubMed CAS Google Scholar
• Wan M, Cao X, Wu Y, Bai S, Wu L, Shi X, Wang N (2002) Jab1 antagonizes TGF-β signaling by inducing Smad4 degradation. EMBO Rep 3:171–176
  PubMed CAS Google Scholar
• Wan M, Tang Y, Tytler EM, Lu C, Jin B, Vickers SM, Yang L, Shi X, Cao X (2004) Smad4 protein stability is regulated by ubiquitin ligase SCF β-TrCP1. J Biol Chem 279:14484–14487
  PubMed CAS Google Scholar
• Watanabe M, Masuyama N, Fukuda M, Nishida E (2000) Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal. EMBO Rep 1:176–182
  PubMed CAS Google Scholar
• Watanabe Y, Itoh S, Goto T, Ohnishi E, Inamitsu M, Itoh F, Satoh K, Wiercinska E, Yang W, Shi L et al (2010) TMEPAI, a transmembrane TGF-β-inducible protein, sequesters Smad proteins from active participation in TGF-β signaling. Mol Cell 37:123–134
  PubMed CAS Google Scholar
• Wicks SJ, Lui S, Abdel-Wahab N, Mason RM, Chantry A (2000) Inactivation of smad-transforming growth factor β signaling by Ca(2+)-calmodulin-dependent protein kinase II. Mol Cell Biol 20:8103–8111
  PubMed CAS Google Scholar
• Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R et al (2001) Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-β signaling. Mol Cell 8:1277–1289
  PubMed CAS Google Scholar
• Wu JW, Krawitz AR, Chai J, Li W, Zhang F, Luo K, Shi Y (2002) Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-β signaling. Cell 111:357–367
  PubMed CAS Google Scholar
• Wu MY, Hill CS (2009) Tgf-β superfamily signaling in embryonic development and homeostasis. Dev Cell 16:329–343
  PubMed CAS Google Scholar
• Wu S, Cetinkaya C, Munoz-Alonso MJ, Lehr N von der, Bahram F, Beuger V, Eilers M, Leon J, Larsson LG (2003) Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene 22:351–360
  PubMed CAS Google Scholar
• Xiao Z, Liu X, Lodish HF (2000) Importin β mediates nuclear translocation of Smad 3. J Biol Chem 275:23425–23428
  PubMed CAS Google Scholar
• Xiao Z, Latek R, Lodish HF (2003) An extended bipartite nuclear localization signal in Smad4 is required for its nuclear import and transcriptional activity. Oncogene 22:1057–1069
  PubMed CAS Google Scholar
• Xin H, Xu X, Li L, Ning H, Rong Y, Shang Y, Wang Y, Fu XY, Chang Z (2005) CHIP controls the sensitivity of transforming growth factor-β signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. J Biol Chem 280:20842–20850
  PubMed CAS Google Scholar
• Xu L, Kang Y, Col S, Massagué J (2002) Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFβ signaling complexes in the cytoplasm and nucleus. Mol Cell 10:271–282
  PubMed CAS Google Scholar
• Xu L, Yao X, Chen X, Lu P, Zhang B, Ip YT (2007) Msk is required for nuclear import of TGF-β/BMP-activated Smads. J Cell Biol 178:981–994
  PubMed CAS Google Scholar
• Xu X, Ehdaie B, Ohara N, Yoshino T, Deng CX (2010) Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene 29:674–686
  PubMed CAS Google Scholar
• Yakymovych I, Dijke P ten, Heldin C-H, Souchelnytskyi S (2001) Regulation of Smad signaling by protein kinase C. FASEB J 15:553–555
  PubMed CAS Google Scholar
• Yang J, Wahdan-Alaswad R, Danielpour D (2009) Critical role of Smad2 in tumor suppression and transforming growth factor-β-induced apoptosis of prostate epithelial cells. Cancer Res 69:2185–2190
  PubMed CAS Google Scholar
• Yao X, Chen X, Cottonham C, Xu L (2008) Preferential utilization of Imp7/8 in nuclear import of Smads. J Biol Chem 283:22867–22874
  PubMed CAS Google Scholar
• Yu J, Pan L, Qin X, Chen H, Xu Y, Chen Y, Tang H (2010) MTMR4 attenuates transforming growth factor β (TGFβ) signaling by dephosphorylating R-Smads in endosomes. J Biol Chem 285:8454–8462
  PubMed CAS Google Scholar
• Zavadil J, Bitzer M, Liang D, Yang YC, Massimi A, Kneitz S, Piek E, Böttinger EP (2001) Genetic programs of epithelial cell plasticity directed by transforming growth factor-β. Proc Natl Acad Sci USA 98:6686–6691
  PubMed CAS Google Scholar
• Zeng Q, Phukan S, Xu Y, Sadim M, Rosman DS, Pennison M, Liao J, Yang GY, Huang CC, Valle L et al (2009) Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development. Cancer Res 69:678–686
  PubMed CAS Google Scholar
• Zhang S, Fei T, Zhang L, Zhang R, Chen F, Ning Y, Han Y, Feng XH, Meng A, Chen YG (2007) Smad7 antagonizes transforming growth factor β signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol Cell Biol 27:4488–4499
  PubMed CAS Google Scholar
• Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R (2001) Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci USA 98:974–979
  PubMed CAS Google Scholar
• Zheng Y, Zhao YD, Gibbons M, Abramova T, Chu PY, Ash JD, Cunningham JM, Skapek SX (2010) Tgfβ signaling directly induces Arf promoter remodeling by a mechanism involving Smads 2/3 and p38 MAPK. J Biol Chem 285:35654–35664
  PubMed CAS Google Scholar
• Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH (1999) A Smad ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400:687–693
  PubMed CAS Google Scholar
• Zhu L, Wang L, Wang X, Luo X, Yang L, Zhang R, Yin H, Xie D, Pan Y, Chen Y (2011) Hepatic deletion of smad7 in mouse leads to spontaneous liver dysfunction and aggravates alcoholic liver injury. PLoS ONE 6:e17415
  PubMed CAS Google Scholar
• Zhu S, Wang W, Clarke DC, Liu X (2007) Activation of Mps1 promotes transforming growth factor-β-independent Smad signaling. J Biol Chem 282:18327–18338
  PubMed CAS Google Scholar

Download references