Skip to main content
SpringerLink
Log in

Transforming Growth Factor-β Signaling

  • Chapter
  • First Online:
TGF-β in Human Disease

Abstract

Members of the transforming growth factor β (TGF-β) family regulate cell proliferation, migration, and differentiation during embryonal development and in tissue homeostasis in the adult. They signal by inducing heteromeric complexes of type I and type II serine/threonine kinase receptors. Ligand binding activates the type I receptor kinase leading to phosphorylation of members of the Smad family, which after oligomerization are translocated to the nucleus where they together with other nuclear factors regulate the transcription of specific genes. TGF-β family members also signal via non-Smad pathways, including Erk, JNK, and p38 MAP-kinase pathways, the tyrosine kinase Src, the small GTPase Rho, and cleavage of the type I receptor whereby the intracellular domain is translocated to the nucleus where it drives an invasiveness program. The TGF-β signaling pathways are carefully regulated by posttranslational mechanisms, including phosphorylation, ubiquitination, acetylation, sumoylation, and PAR-ylation, as well as by positive and negative feedback mechanisms and cross talk with other signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agricola E, Randall RA, Gaarenstroom T et al (2011) Recruitment of TIF1γ to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. Mol Cell 43:85–96

    PubMed  CAS  Google Scholar 

  • Ahn SM, Cha JY, Kim J et al (2012) Smad3 regulates E-cadherin via miRNA-200 pathway. Oncogene 31:3051–3059

    PubMed  CAS  Google Scholar 

  • Akiyoshi S, Inoue H, Hanai J et al (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 et al (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell 139:757–769

    PubMed  Google Scholar 

  • Ameln AK, Muschter A, Mamlouk S et al (2011) Inhibition of HIF prolyl hydroxylase-2 blocks tumor growth in mice through the antiproliferative activity of TGFβ. Cancer Res 71:3306–3316

    Google Scholar 

  • Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFβ activation. J Cell Sci 116:217–224

    PubMed  CAS  Google Scholar 

  • Aoyagi-Ikeda K, Maeno T, Matsui H et al (2011) Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-β-Smad3 pathway. Am J Respir Cell Mol Biol 45:136–144

    PubMed  CAS  Google Scholar 

  • Aragon E, Goerner N, Zaromytidou AI et al (2011) A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev 25:1275–1288

    PubMed  CAS  Google Scholar 

  • Bandyopadhyay B, Han A, Dai J et al (2011) TβRI/Alk5-independent TβRII signaling to ERK1/2 in human skin cells according to distinct levels of TβRII expression. J Cell Sci 124:19–24

    PubMed  CAS  Google Scholar 

  • Batut J, Howell M, Hill CS (2007) Kinesin-mediated transport of Smad2 is required for signaling in response to TGF-β ligands. Dev Cell 12:261–274

    PubMed  CAS  Google Scholar 

  • Batut J, Schmierer B, Cao J et al (2008) Two highly related regulatory subunits of PP2A exert opposite effects on TGF-β/Activin/Nodal signalling. Development 135:2927–2937

    PubMed  CAS  Google Scholar 

  • Bengoechea-Alonso MT, Ericsson J (2010) Tumor suppressor Fbxw7 regulates TGFβ signaling by targeting TGIF1 for degradation. Oncogene 29:5322–5328

    PubMed  CAS  Google Scholar 

  • Benus GF, Wierenga AT, de Gorter DJ et al (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 

  • Bizet AA, Tran-Khanh N, Saksena A et al (2012) CD109-mediated degradation of TGF-β receptors and inhibition of TGF-β responses involve regulation of SMAD7 and Smurf2 localization and function. J Cell Biochem 113:238–246

    PubMed  CAS  Google Scholar 

  • Buscemi L, Ramonet D, Klingberg F et al (2011) The single-molecule mechanics of the latent TGF-β1 complex. Curr Biol 21:2046–2054

    PubMed  CAS  Google Scholar 

  • Chandra M, Zang S, Li H et al (2012) Nuclear translocation of type I transforming growth factor β receptor confers a novel function in RNA processing. Mol Cell Biol 32:2183–2195

    PubMed  CAS  Google Scholar 

  • Chang CC, Lin DY, Fang HI et al (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 et al (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 

  • Clarke DC, Brown ML, Erickson RA et al (2009) Transforming growth factor β depletion is the primary determinant of Smad signaling kinetics. Mol Cell Biol 29:2443–2455

    PubMed  CAS  Google Scholar 

  • Dai F, Lin X, Chang C, Feng XH (2009) Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-β signaling. Dev Cell 16:345–357

    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 et al (2010) Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell 39:373–384

    PubMed  CAS  Google Scholar 

  • Davis-Dusenbery BN, Chan MC, Reno KE et al (2011) Down-regulation of Krüppel-like factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-β and bone morphogenetic protein 4. J Biol Chem 286:28097–28110

    PubMed  CAS  Google Scholar 

  • de Caestecker MP, Parks WT, Frank CJ et al (1998) Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev 12:1587–1592

    PubMed  Google Scholar 

  • de Graauw M, van Miltenburg MH, Schmidt MK et al (2010) Annexin A1 regulates TGF-β signaling and promotes metastasis formation of basal-like breast cancer cells. Proc Natl Acad Sci USA 107:6340–6345

    PubMed  Google Scholar 

  • Dennler S, Itoh S, Vivien D et al (1998) Direct binding of Smad3 and Smad4 to critical TGF-β-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 17:3091–3100

    PubMed  CAS  Google Scholar 

  • Derynck R, Miyazono K (eds) (2007) The TGF-β family. Cold Spring Harbor Laboratory Press, New York

    Google Scholar 

  • Descargues P, Sil AK, Sano Y et al (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 

  • Dong C, Li Z, Alvarez R Jr et al (2000) Microtubule binding to Smads may regulate TGFβ activity. Mol Cell 5:27–34

    PubMed  CAS  Google Scholar 

  • Duan X, Liang YY, Feng XH, Lin X (2006) Protein serine/threonine phosphatase PPM1A dephosphorylates Smad1 in the bone morphogenetic protein signaling pathway. J Biol Chem 281:36526–36532

    PubMed  CAS  Google Scholar 

  • Dupont S, Zacchigna L, Cordenonsi M et al (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 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 et al (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 

  • Edlund S, Landström M, Heldin C-H, Aspenström P (2002) Transforming growth factor-β-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell 13:902–914

    PubMed  CAS  Google Scholar 

  • Edlund S, Bu S, Schuster N et al (2003) Transforming growth factor-β1 (TGF-β)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-β-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell 14:529–544

    PubMed  CAS  Google Scholar 

  • Edlund S, Landström M, Heldin C-H, Aspenström P (2004) Smad7 is required for TGF-β-induced activation of the small GTPase Cdc42. J Cell Sci 117:1835–1847

    PubMed  CAS  Google Scholar 

  • Edlund S, Lee SY, Grimsby S et al (2005) Interaction between Smad7 and β-catenin: importance for transforming growth factor β-induced apoptosis. Mol Cell Biol 25:1475–1488

    PubMed  CAS  Google Scholar 

  • Eichhorn PJ, Rodon L, Gonzalez-Junca A et al (2012) USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med 18:429–435

    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 

  • Fischer AN, Fuchs E, Mikula M et al (2007) PDGF essentially links TGF-β signaling to nuclear β-catenin accumulation in hepatocellular carcinoma progression. Oncogene 26:3395–3405

    PubMed  CAS  Google Scholar 

  • Fukuchi M, Imamura T, Chiba T et al (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 

  • Gal A, Sjöblom T, Fedorova L et al (2008) Sustained TGF-β exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene 27:1218–1230

    PubMed  CAS  Google Scholar 

  • Gao S, Alarcon C, Sapkota G et al (2009) Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling. Mol Cell 36:457–468

    PubMed  CAS  Google Scholar 

  • Gomis RR, Alarcon C, He W et al (2006) A FoxO-Smad synexpression group in human keratinocytes. Proc Natl Acad Sci USA 103:12747–12752

    PubMed  CAS  Google Scholar 

  • Gotzmann J, Fischer AN, Zojer M et al (2006) A crucial function of PDGF in TGF-β-mediated cancer progression of hepatocytes. Oncogene 25:3170–3185

    PubMed  CAS  Google Scholar 

  • Goumans M-J, Valdimarsdottir G, Itoh S et al (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 

  • 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 

  • Gu AD, Wang Y, Lin L et al (2012) Requirements of transcription factor Smad-dependent and independent TGF-β signaling to control discrete T-cell functions. Proc Natl Acad Sci USA 109:905–910

    PubMed  CAS  Google Scholar 

  • Guo X, Ramirez A, Waddell DS et al (2008) Axin and GSK3-control Smad3 protein stability and modulate TGF-β signaling. Genes Dev 22:106–120

    PubMed  CAS  Google Scholar 

  • Häger M, Pedersen CC, Larsen MT et al (2011) MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-β1 stimulation in granulocytic precursors. Blood 118:6649–6659

    PubMed  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 et al (2010) Epigenetic downregulation of human disabled homolog 2 switches TGFβ from a tumor suppressor to a tumor promoter. J Clin Invest 120:2842–2857

    PubMed  CAS  Google Scholar 

  • Hayashi H, Abdollah S, Qiu Y 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 et al (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 et al (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 et al (2010b) Hypoxia-activated Smad3-specific dephosphorylation by PP2A. J Biol Chem 285:3740–3749

    PubMed  CAS  Google Scholar 

  • Heldin C-H, Vanlandewijck M, Moustakas A (2012) Regulation of EMT by TGFβ in cancer. FEBS Lett 586:1959–1970

    PubMed  CAS  Google Scholar 

  • Hesling C, Fattet L, Teyre G et al (2011) Antagonistic regulation of EMT by TIF1γ and Smad4 in mammary epithelial cells. EMBO Rep 12:665–672

    PubMed  CAS  Google Scholar 

  • Ho J, Cocolakis E, Dumas VM et al (2005) The G protein-coupled receptor kinase-2 is a TGF-β-inducible antagonist of TGFβ signal transduction. EMBO J 24:3247–3258

    PubMed  CAS  Google Scholar 

  • Hofmann TG, Stollberg N, Schmitz ML, Will H (2003) HIPK2 regulates transforming growth factor-β-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells. Cancer Res 63:8271–8277

    PubMed  CAS  Google Scholar 

  • Holm TM, Habashi JP, Doyle JJ et al (2011) Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332:358–361

    PubMed  CAS  Google Scholar 

  • Horiguchi K, Sakamoto K, Koinuma D et al (2012) TGF-β drives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP. Oncogene 31:3190–3201

    PubMed  CAS  Google Scholar 

  • Hu D, Wan Y (2011) Regulation of Kruppel-like factor 4 by the anaphase promoting complex pathway is involved in TGF-β signaling. J Biol Chem 286:6890–6901

    PubMed  CAS  Google Scholar 

  • Hu H, Milstein M, Bliss JM et al (2008) Integration of transforming growth factor β and RAS signaling silences a RAB5 guanine nucleotide exchange factor and enhances growth factor-directed cell migration. Mol Cell Biol 28:1573–1583

    PubMed  CAS  Google Scholar 

  • Hua F, Mu R, Liu J et al (2011) TRB3 interacts with SMAD3 promoting tumor cell migration and invasion. J Cell Sci 124:3235–3246

    PubMed  CAS  Google Scholar 

  • Huang T, David L, Mendoza V et al (2011) TGF-β signalling is mediated by two autonomously functioning TβRI:TβRII pairs. EMBO J 30:1263–1276

    PubMed  CAS  Google Scholar 

  • Hyytiäinen M, Penttinen C, Keski-Oja J (2004) Latent TGF-β binding proteins: extracellular matrix association and roles in TGF-β activation. Crit Rev Clin Lab Sci 41:233–264

    PubMed  Google Scholar 

  • Ikushima H, Komuro A, Isogaya K et al (2008) An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-β signalling. EMBO J 27:2955–2965

    PubMed  CAS  Google Scholar 

  • Imoto S, Ohbayashi N, Ikeda O et al (2008) Sumoylation of Smad3 stimulates its nuclear export during PIASy-mediated suppression of TGF-β signaling. Biochem Biophys Res Commun 370:359–365

    PubMed  CAS  Google Scholar 

  • Inman GJ, Nicolas FJ, Hill CS (2002) Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-β receptor activity. Mol Cell 10:283–294

    PubMed  CAS  Google Scholar 

  • Inui M, Manfrin A, Mamidi A et al (2011) USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol 13:1368–1375

    PubMed  CAS  Google Scholar 

  • Itoh S, Landström M, Hermansson A et al (1998) Transforming growth factor β1 induces nuclear export of inhibitory Smad7. J Biol Chem 273:29195–29201

    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 

  • Kaneko S, Chen X, Lu P et al (2011) Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci USA 108:11127–11132

    PubMed  CAS  Google Scholar 

  • Kang JS, Saunier EF, Akhurst RJ, Derynck R (2008) The type I TGF-β receptor is covalently modified and regulated by sumoylation. Nat Cell Biol 10:654–664

    PubMed  CAS  Google Scholar 

  • Kavsak P, Rasmussen RK, Causing CG et al (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 et al (2009) 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 

  • Koinuma D, Shinozaki M, Komuro A 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 et al (2009) Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor β signaling. Mol Cell Biol 29:172–186

    PubMed  CAS  Google Scholar 

  • Koinuma D, Shinozaki M, Nagano Y et al (2011) RB1CC1 protein positively regulates transforming growth factor-β signaling through the modulation of Arkadia E3 ubiquitin ligase activity. J Biol Chem 286:32502–32512

    PubMed  CAS  Google Scholar 

  • Komuro A, Imamura T, Saitoh M et al (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 

  • Kowanetz M, Valcourt U, Bergström R et al (2004) Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor β and bone morphogenetic protein. Mol Cell Biol 24:4241–4254

    PubMed  CAS  Google Scholar 

  • Kowanetz M, Lönn P, Vanlandewijck M et al (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 TGF-β/Smad signaling by oncogenic Ras. Genes Dev 13:804–816

    PubMed  CAS  Google Scholar 

  • Kuratomi G, Komuro A, Goto K et al (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 et al (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 et al (2006) The mechanism of nuclear export of Smad3 involves exportin 4 and Ran. Mol Cell Biol 26:1318–1332

    PubMed  CAS  Google Scholar 

  • Kwon S, Christian JL (2011) Sortilin associates with transforming growth factor-β family proteins to enhance lysosome-mediated degradation. J Biol Chem 286:21876–21885

    PubMed  CAS  Google Scholar 

  • Lallemand F, Seo SR, Ferrand N et al (2005) AIP4 restricts transforming growth factor-β signaling through a ubiquitination-independent mechanism. J Biol Chem 280:27645–27653

    PubMed  CAS  Google Scholar 

  • Lamouille S, Derynck R (2007) Cell size and invasion in TGF-β-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol 178:437–451

    PubMed  CAS  Google Scholar 

  • Lamouille S, Connolly E, Smyth JW et al (2012) TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci 125:1259–1273

    PubMed  CAS  Google Scholar 

  • Le Scolan E, Zhu Q, Wang L et al (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 

  • 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 

  • Lee B-H, Chen W, Stippec S, Cobb MH (2007a) 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 MK, Pardoux C, Hall MC et al (2007b) TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J 26:3957–3967

    PubMed  CAS  Google Scholar 

  • Lee J, Moon HJ, Lee JM, Joo CK (2010) Smad3 regulates Rho signaling via NET1 in the transforming growth factor-β-induced epithelial-mesenchymal transition of human retinal pigment epithelial cells. J Biol Chem 285:26618–26627

    PubMed  CAS  Google Scholar 

  • Levy L, Howell M, Das D et al (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 et al (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 et al (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 et al (2006) PPM1A functions as a Smad phosphatase to terminate TGFβ signaling. Cell 125:915–928

    PubMed  CAS  Google Scholar 

  • Liu Z, Lin X, Cai Z et al (2011) Global identification of SMAD2 target genes reveals a role for multiple co-regulatory factors in zebrafish early gastrulas. J Biol Chem 286:28520–28532

    PubMed  CAS  Google Scholar 

  • Liu YN, Abou-Kheir W, Yin JJ et al (2012) Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition. Mol Cell Biol 32:941–953

    PubMed  Google Scholar 

  • Long X, Miano JM (2011) Transforming growth factor-β1 (TGF-β1) utilizes distinct pathways for the transcriptional activation of microRNA 143/145 in human coronary artery smooth muscle cells. J Biol Chem 286:30119–30129

    PubMed  CAS  Google Scholar 

  • Lönn P, van der Heide L, Dahl M et al (2010) PARP-1 attenuates Smad-mediated transcription. Mol Cell 40:521–532

    PubMed  Google Scholar 

  • Lönn P, Vanlandewijck M, Raja E et al (2012) Transcriptional induction of salt-inducible kinase 1 by transforming growth factor β leads to negative regulation of type I receptor signaling in cooperation with the Smurf2 ubiquitin ligase. J Biol Chem 287:12867–12878

    PubMed  Google Scholar 

  • López-Casillas F, Payne HM, Andres JL, Massagué J (1994) Betaglycan can act as a dual modulator of TGF-β access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol 124:557–568

    PubMed  Google Scholar 

  • Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010) MicroRNA-155 targets SMAD2 and modulates the response of macrophages to transforming growth factor-β. J Biol Chem 285:41328–41336

    PubMed  CAS  Google Scholar 

  • Luo K, Stroschein SL, Wang W et al (1999) The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling. Genes Dev 13:2196–2206

    PubMed  CAS  Google Scholar 

  • Massagué J (2004) G1 cell-cycle control and cancer. Nature 432:298–306

    PubMed  Google Scholar 

  • Matsuura I, Denissova NG, Wang G et al (2004) Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430:226–231

    PubMed  CAS  Google Scholar 

  • Matsuura I, Chiang KN, Lai CY et al (2010) Pin1 promotes transforming growth factor-β-induced migration and invasion. J Biol Chem 285:1754–1764

    PubMed  CAS  Google Scholar 

  • Millet C, Yamashita M, Heller M et al (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 

  • Mizutani A, Koinuma D, Tsutsumi S et al (2011) Cell type-specific target selection by combinatorial binding of Smad2/3 proteins and hepatocyte nuclear factor 4α in HepG2 cells. J Biol Chem 286:29848–29860

    PubMed  CAS  Google Scholar 

  • Morén A, Hellman U, Inada Y et al (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 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 (2009) The regulation of TGFβ signal transduction. Development 136:3699–3714

    PubMed  CAS  Google Scholar 

  • Moustakas A, Heldin C-H (2012) Induction of epithelial-mesenchymal transition by transforming growth factor β. Semin Cancer Biol 22:446–454

    PubMed  CAS  Google Scholar 

  • Mu Y, Sundar R, Thakur N et al (2011) TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer. Nat Commun 2:330

    PubMed  Google Scholar 

  • Mulder KM (2000) Role of Ras and Mapks in TGFβ signaling. Cytokine Growth Factor Rev 11:23–35

    PubMed  CAS  Google Scholar 

  • Mullen AC, Orlando DA, Newman JJ et al (2011) Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell 147:565–576

    PubMed  CAS  Google Scholar 

  • Nagano Y, Mavrakis KJ, Lee KL 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 

  • Nakano A, Koinuma D, Miyazawa 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 et al (1997) Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389:631–635

    PubMed  CAS  Google Scholar 

  • Nicolas FJ, De Bosscher K, Schmierer B, Hill CS (2004) Analysis of Smad nucleocytoplasmic shuttling in living cells. J Cell Sci 117:4113–4125

    PubMed  CAS  Google Scholar 

  • Niimi H, Pardali K, Vanlandewijck M et al (2007) Notch signaling is necessary for epithelial growth arrest by TGF-β. J Cell Biol 176:695–707

    PubMed  CAS  Google Scholar 

  • Nishimura SL (2009) Integrin-mediated transforming growth factor-β activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol 175:1362–1370

    PubMed  CAS  Google Scholar 

  • Ohashi S, Natsuizaka M, Naganuma S et al (2011) A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors. Cancer Res 71:6836–6847

    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 

  • Ozdamar B, Bose R, Barrios-Rodiles M et al (2005) Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307:1603–1609

    PubMed  CAS  Google Scholar 

  • Papadimitriou E, Vasilaki E, Vorvis C et al (2012) Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-β and miR-24: role in epithelial-to-mesenchymal transition. Oncogene 31:2862–2875

    PubMed  CAS  Google Scholar 

  • Pardali E, Goumans MJ, ten Dijke P (2010) Signaling by members of the TGF-β family in vascular morphogenesis and disease. Trends Cell Biol 20:556–567

    PubMed  CAS  Google Scholar 

  • Park SS, Eom YW, Kim EH et al (2004) Involvement of c-Src kinase in the regulation of TGF-β1-induced apoptosis. Oncogene 23:6272–6281

    PubMed  CAS  Google Scholar 

  • Penheiter SG, Mitchell H, Garamszegi N et al (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 

  • Perlman R, Schiemann WP, Brooks MW et al (2001) TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 3:708–714

    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 

  • Qiu T, Wu X, Zhang F et al (2010) TGF-β type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat Cell Biol 12:224–234

    PubMed  CAS  Google Scholar 

  • Roelen BA, Cohen OS, Raychowdhury MK et al (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 

  • Sadej R, Romanska H, Kavanagh D et al (2010) Tetraspanin CD151 regulates transforming growth factor β signaling: implication in tumor metastasis. Cancer Res 70:6059–6070

    PubMed  CAS  Google Scholar 

  • Sapkota G, Knockaert M, Alarcon C et al (2006) Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-β pathways. J Biol Chem 281:40412–40419

    PubMed  CAS  Google Scholar 

  • Schmierer B, Hill CS (2005) Kinetic analysis of Smad nucleocytoplasmic shuttling reveals a mechanism for transforming growth factor β-dependent nuclear accumulation of Smads. Mol Cell Biol 25:9845–9858

    PubMed  CAS  Google Scholar 

  • Schmierer B, Hill CS (2007) TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8:970–982

    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 et al (2004) The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. EMBO J 23:3780–3792

    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 

  • Sflomos G, Kostaras E, Panopoulou E et al (2011) ERBIN is a new SARA-interacting protein: competition between SARA and SMAD2 and SMAD3 for binding to ERBIN. J Cell Sci 124:3209–3222

    PubMed  CAS  Google Scholar 

  • Sharma V, Antonacopoulou AG, Tanaka S et al (2011) Enhancement of TGF-β signaling responses by the E3 ubiquitin ligase Arkadia provides tumor suppression in colorectal cancer. Cancer Res 71:6438–6449

    PubMed  CAS  Google Scholar 

  • Shen X, Li J, Hu PP et al (2001) The activity of guanine exchange factor NET1 is essential for transforming growth factor-β-mediated stress fiber formation. J Biol Chem 276:15362–15368

    PubMed  CAS  Google Scholar 

  • Shi Y, Wang YF, Jayaraman L et al (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 

  • Shi W, Sun C, He B et al (2004) GADD34-PP1c recruited by Smad7 dephosphorylates TGFβ type I receptor. J Cell Biol 164:291–300

    PubMed  CAS  Google Scholar 

  • Shi M, Zhu J, Wang R et al (2011) Latent TGF-β structure and activation. Nature 474:343–349

    PubMed  CAS  Google Scholar 

  • Shirakihara T, Horiguchi K, Miyazawa K et al (2011) TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J 30:783–795

    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 et al (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 

  • 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 30:2451–2462

    PubMed  CAS  Google Scholar 

  • Sorrentino A, Thakur N, Grimsby S et al (2008) The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol 10:1199–1207

    PubMed  CAS  Google Scholar 

  • Stroschein SL, Wang W, Zhou SL et al (1999) Negative feedback regulation of TGF-β signaling by the SnoN oncoprotein. Science 286:771–774

    PubMed  CAS  Google Scholar 

  • Sun H, Li D, Chen S et al (2010) Zili inhibits transforming growth factor-β signaling by interacting with Smad4. J Biol Chem 285:4243–4250

    PubMed  CAS  Google Scholar 

  • Tajima Y, Goto K, Yoshida M et al (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 

  • Tam BY, Finnson KW, Philip A (2003) Glycosylphosphatidylinositol-anchored proteins regulate transforming growth factor-β signaling in human keratinocytes. J Biol Chem 278:49610–49617

    PubMed  CAS  Google Scholar 

  • Tanaka Y, Kobayashi H, Suzuki M et al (2004) Transforming growth factor-β1-dependent urokinase up-regulation and promotion of invasion are involved in Src-MAPK-dependent signaling in human ovarian cancer cells. J Biol Chem 279:8567–8576

    PubMed  CAS  Google Scholar 

  • Tang LY, Yamashita M, Coussens NP et al (2011) Ablation of Smurf2 reveals an inhibition in TGF-β signalling through multiple mono-ubiquitination of Smad3. EMBO J 30:4777–4789

    PubMed  CAS  Google Scholar 

  • Thillainadesan G, Chitilian JM, Isovic M et al (2012) TGF-β-dependent active demethylation and expression of the p15ink4b tumor suppressor are impaired by the ZNF217/CoREST complex. Mol Cell 46:636–649

    PubMed  CAS  Google Scholar 

  • Tsukazaki T, Chiang TA, Davison AF et al (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 

  • Vardouli L, Moustakas A, Stournaras C (2005) LIM-kinase 2 and cofilin phosphorylation mediate actin cytoskeleton reorganization induced by transforming growth factor-β. J Biol Chem 280:11448–11457

    PubMed  CAS  Google Scholar 

  • Varelas X, Sakuma R, Samavarchi-Tehrani P et al (2008) TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10:837–848

    PubMed  CAS  Google Scholar 

  • Varelas X, Samavarchi-Tehrani P, Narimatsu M et al (2010) The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev Cell 19:831–844

    PubMed  CAS  Google Scholar 

  • Vincent T, Neve EPA, Johnson JR 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 

  • Wakabayashi Y, Tamiya T, Takada I et al (2011) Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-β-Smad pathway. J Biol Chem 286:35456–35465

    PubMed  CAS  Google Scholar 

  • Wan M, Cao X, Wu Y et al (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 et al (2004) Smad4 protein stability is regulated by ubiquitin ligase SCF β-TrCP1. J Biol Chem 279:14484–14487

    PubMed  CAS  Google Scholar 

  • Warzecha CC, Sato TK, Nabet B et al (2009) ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 33:591–601

    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 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 et al (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 

  • Wicks SJ, Haros K, Maillard M et al (2005) The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-β signalling. Oncogene 24:8080–8084

    PubMed  CAS  Google Scholar 

  • Wotton D, Lo RS, Lee S, Massagué J (1999a) A Smad transcriptional corepressor. Cell 97:29–39

    PubMed  CAS  Google Scholar 

  • Wotton D, Lo RS, Swaby LA, Massague J (1999b) Multiple modes of repression by the Smad transcriptional corepressor TGIF. J Biol Chem 274:37105–37110

    PubMed  CAS  Google Scholar 

  • Wotton D, Knoepfler PS, Laherty CD et al (2001) The Smad transcriptional corepressor TGIF recruits mSin3. Cell Growth Differ 12:457–463

    PubMed  CAS  Google Scholar 

  • Wrana JL, Attisano L, Wieser R et al (1994) Mechanism of activation of the TGF-β receptor. Nature 370:341–347

    PubMed  CAS  Google Scholar 

  • Wrighton KH, Willis D, Long J et al (2006) Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-β signaling. J Biol Chem 281:38365–38375

    PubMed  CAS  Google Scholar 

  • Wrighton KH, Lin X, Feng XH (2008) Critical regulation of TGFβ signaling by Hsp90. Proc Natl Acad Sci USA 105:9244–9249

    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 JW, Krawitz AR, Chai J et al (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 

  • Xi Q, He W, Zhang XH et al (2008) Genome-wide impact of the BRG1 SWI/SNF chromatin remodeler on the transforming growth factor β transcriptional program. J Biol Chem 283:1146–1155

    PubMed  CAS  Google Scholar 

  • Xi Q, Wang Z, Zaromytidou AI et al (2011) A poised chromatin platform for TGF-β access to master regulators. Cell 147:1511–1524

    PubMed  CAS  Google Scholar 

  • Xiao Z, Liu X, Henis YI, Lodish HF (2000a) A distinct nuclear localization signal in the N terminus of Smad 3 determines its ligand-induced nuclear translocation. Proc Natl Acad Sci USA 97:7853–7858

    PubMed  CAS  Google Scholar 

  • Xiao Z, Liu X, Lodish HF (2000b) 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 et al (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, Chen YG, Massagué J (2000) The nuclear import function of Smad2 is masked by SARA and unmasked by TGFβ-dependent phosphorylation. Nat Cell Biol 2:559–562

    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, Alarcon C, Col S, Massague J (2003) Distinct domain utilization by Smad3 and Smad4 for nucleoporin interaction and nuclear import. J Biol Chem 278:42569–42577

    PubMed  CAS  Google Scholar 

  • Xu L, Yao X, Chen X et al (2007) Msk is required for nuclear import of TGFβ/BMP-activated Smads. J Cell Biol 178:981–994

    PubMed  CAS  Google Scholar 

  • Xue G, Restuccia DF, Lan Q et al (2012) Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGFβ signaling axes. Cancer Discov 2:248–259

    PubMed  CAS  Google Scholar 

  • Yagi K, Goto D, Hamamoto T et al (1999) Alternatively spliced variant of Smad2 lacking exon 3. Comparison with wild-type Smad2 and Smad3. J Biol Chem 274:703–709

    PubMed  CAS  Google Scholar 

  • Yakymovych I, ten Dijke P, Heldin C-H, Souchelnytskyi S (2001) Regulation of Smad signaling by protein kinase C. FASEB J 15:553–555

    PubMed  CAS  Google Scholar 

  • Yamashita M, Fatyol K, Jin C et al (2008) TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-β. Mol Cell 31:918–924

    PubMed  CAS  Google Scholar 

  • Yan X, Zhang J, Pan L et al (2011) TSC-22 promotes transforming growth factor β-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity. Mol Cell Biol 31:3700–3709

    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 

  • Yi JY, Shin I, Arteaga CL (2005) Type I transforming growth factor β receptor binds to and activates phosphatidylinositol 3-kinase. J Biol Chem 280:10870–10876

    PubMed  CAS  Google Scholar 

  • Yilmaz M, Maass D, Tiwari N et al (2011) Transcription factor Dlx2 protects from TGFβ-induced cell-cycle arrest and apoptosis. EMBO J 30:4489–4499

    PubMed  CAS  Google Scholar 

  • Yu J, Pan L, Qin X et al (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, Cermak L, Soto-Nieves N, Bottinger EP (2004) Integration of TGF-β/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23:1155–1165

    PubMed  CAS  Google Scholar 

  • Zawel L, Dai JL, Buckhaults P et al (1998) Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1:611–617

    PubMed  CAS  Google Scholar 

  • Zhang Y, Chang C, Gehling DJ et al (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 

  • Zhang L, Fujita T, Wu G et al (2011) Phosphorylation of the anaphase-promoting complex/Cdc27 is involved in TGF-β signaling. J Biol Chem 286:10041–10050

    PubMed  CAS  Google Scholar 

  • Zhang L, Huang H, Zhou F et al (2012a) RNF12 controls embryonic stem cell fate and morphogenesis in zebrafish embryos by targeting Smad7 for degradation. Mol Cell 46:650–661

    PubMed  CAS  Google Scholar 

  • Zhang L, Zhou F, Drabsch Y et al (2012b) USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor. Nat Cell Biol 14:717–726

    PubMed  CAS  Google Scholar 

  • Zhao Y, Thornton AM, Kinney MC et al (2011) The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor β (TGF-β) signaling and the development of regulatory T cells. J Biol Chem 286:40520–40530

    PubMed  CAS  Google Scholar 

  • Zhou Q, Fan J, Ding X et al (2010) TGF-β-induced MiR-491-5p expression promotes Par-3 degradation in rat proximal tubular epithelial cells. J Biol Chem 285:40019–40027

    PubMed  CAS  Google Scholar 

  • Zhou B, Liu Y, Kahn M et al (2012) Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem 287:7026–7038

    PubMed  CAS  Google Scholar 

  • Zhu H, Kavsak P, Abdollah S et al (1999) A Smad ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400:687–693

    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

Acknowledgment

Ingegärd Schiller is gratefully acknowledged for valuable help in the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 595, SE-751 24, Uppsala, Sweden

    Carl-Henrik Heldin

Authors
  1. Carl-Henrik Heldin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carl-Henrik Heldin .

Editor information

Editors and Affiliations

  1. , Dept Medical Biochem Microbiol, Uppsala University, Box 582, Uppsala, SE-751 23, Sweden

    Aristidis Moustakas

  2. , Interdiscip. Grad. Sch. Med. Eng., University of Yamanashi, 1110 Shimokato, Chuo, 409-3898, Yamanashi, Japan

    Keiji Miyazawa

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer

About this chapter

Cite this chapter

Heldin, CH. (2013). Transforming Growth Factor-β Signaling. In: Moustakas, A., Miyazawa, K. (eds) TGF-β in Human Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54409-8_1

Download citation

Publish with us

Policies and ethics

Search

Navigation