Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition.

Members of the transforming growth factor-beta (TGF-beta) family have important roles during embryogenesis, as well as in the control of tissue homeostasis in the adult. They exert their cellular effects via binding to serine/threonine kinase receptors. Members of the Smad family of transcription factors are important intracellular messengers, and recent studies have shown that the ubiquitin ligase TRAF6 mediates other specific signals. TGF-beta signaling is tightly controlled by post-translational modifications, which regulate the activity, stability, and subcellular localization of the signaling components. The aim of this review is to summarize some of the recent findings on the mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition.

[1]  A. Karsan,et al.  Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. , 2007, The Journal of experimental medicine.

[2]  K. Venkatasubbarao,et al.  Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. , 2008, Cancer research.

[3]  J. Alcorn,et al.  Jun N-terminal kinase 1 regulates epithelial-to-mesenchymal transition induced by TGF-β1 , 2008, Journal of Cell Science.

[4]  E. Hay,et al.  TGFβ3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex , 2007, Journal of Cell Science.

[5]  J. Massagué,et al.  TGFβ in Cancer , 2008, Cell.

[6]  Malte Buchholz,et al.  Sp1 is required for transforming growth factor-beta-induced mesenchymal transition and migration in pancreatic cancer cells. , 2007, Cancer research.

[7]  R. Derynck,et al.  The TGF-β Family , 2008 .

[8]  Takeshi Imamura,et al.  Role of Ras Signaling in the Induction of Snail by Transforming Growth Factor-β* , 2009, Journal of Biological Chemistry.

[9]  S. Aizawa,et al.  EPB41L5 functions to post-transcriptionally regulate cadherin and integrin during epithelial–mesenchymal transition , 2008, The Journal of cell biology.

[10]  Atsushi Miyawaki,et al.  Visualizing Spatiotemporal Dynamics of Multicellular Cell-Cycle Progression , 2008, Cell.

[11]  Liang Xie,et al.  Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. , 2007, Cancer research.

[12]  Stephen W. Michnick,et al.  PKB/Akt modulates TGF-β signalling through a direct interaction with Smad3 , 2004, Nature Cell Biology.

[13]  W. Schiemann,et al.  Src phosphorylates Tyr284 in tgf-β type II receptor and regulates TGF-β stimulation of p38 MAPK during breast cancer cell proliferation and invasion , 2007 .

[14]  M. Howell,et al.  Arkadia Activates Smad3/Smad4-Dependent Transcription by Triggering Signal-Induced SnoN Degradation , 2007, Molecular and Cellular Biology.

[15]  Jonas Larsson,et al.  Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. , 2003, Molecular cell.

[16]  Kohei Miyazono,et al.  Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β , 2007 .

[17]  G. Blobe,et al.  Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. , 2008, Carcinogenesis.

[18]  M. Karin,et al.  IKKα is a critical coregulator of a Smad4-independent TGFβ-Smad2/3 signaling pathway that controls keratinocyte differentiation , 2008, Proceedings of the National Academy of Sciences.

[19]  M. Reiss,et al.  Transforming growth factor beta type I receptor kinase mutant associated with metastatic breast cancer. , 1998, Cancer research.

[20]  Xuedong Liu,et al.  Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. , 2008, Genes & development.

[21]  G. Wildey,et al.  TGFβ‐mediated BIM expression and apoptosis are regulated through SMAD3‐dependent expression of the MAPK phosphatase MKP2 , 2008, EMBO reports.

[22]  Pamela A. Hoodless,et al.  Slug is a direct Notch target required for initiation of cardiac cushion cellularization , 2008, The Journal of cell biology.

[23]  C. Steindler,et al.  TGFβ-induced EMT requires focal adhesion kinase (FAK) signaling , 2008 .

[24]  J. Keski‐Oja,et al.  Epilysin (MMP-28) induces TGF-β mediated epithelial to mesenchymal transition in lung carcinoma cells , 2006, Journal of Cell Science.

[25]  E. Robertis,et al.  Integrating Patterning Signals: Wnt/GSK3 Regulates the Duration of the BMP/Smad1 Signal , 2007, Cell.

[26]  N. Liberati,et al.  Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-β signaling , 2008, Oncogene.

[27]  G. Goodall,et al.  The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1 , 2008, Nature Cell Biology.

[28]  W. Liu,et al.  Downregulation of Par-3 expression and disruption of Par complex integrity by TGF-beta during the process of epithelial to mesenchymal transition in rat proximal epithelial cells. , 2008, Biochimica et biophysica acta.

[29]  T. Brabletz,et al.  A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells , 2008, EMBO reports.

[30]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[31]  J. Zavadil,et al.  Transforming Growth Factor-β and microRNA:mRNA Regulatory Networks in Epithelial Plasticity , 2007, Cells Tissues Organs.

[32]  Konstantinos J. Mavrakis,et al.  Arkadia Enhances Nodal/TGF-β Signaling by Coupling Phospho-Smad2/3 Activity and Turnover , 2007, PLoS biology.

[33]  R. Derynck,et al.  The type I TGF-β receptor is covalently modified and regulated by sumoylation , 2008, Nature Cell Biology.

[34]  M. Reiss,et al.  Novel inactivating mutations of transforming growth factor‐β type I receptor gene in head‐and‐neck cancer metastases , 2001, International journal of cancer.

[35]  Domenico Coppola,et al.  MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA , 2008, Molecular and Cellular Biology.

[36]  E. Bottinger,et al.  Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. , 2008, The Journal of clinical investigation.

[37]  Samy Lamouille,et al.  Cell size and invasion in TGF-β–induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway , 2007, The Journal of cell biology.

[38]  K. Luo,et al.  Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis , 2004, Nature Cell Biology.

[39]  C. Heldin,et al.  HMGA2 and Smads Co-regulate SNAIL1 Expression during Induction of Epithelial-to-Mesenchymal Transition* , 2008, Journal of Biological Chemistry.

[40]  R. Randall,et al.  Transforming Growth Factor (cid:2) -Induced Smad1/5 Phosphorylation in Epithelial Cells Is Mediated by Novel Receptor Complexes and Is Essential for Anchorage-Independent Growth (cid:1) † , 2022 .

[41]  Liliana Attisano,et al.  SARA, a FYVE Domain Protein that Recruits Smad2 to the TGFβ Receptor , 1998, Cell.

[42]  A. Brivanlou,et al.  Balancing BMP signaling through integrated inputs into the Smad1 linker. , 2007, Molecular cell.

[43]  Hui Wang,et al.  Novel roles of Akt and mTOR in suppressing TGF‐β/ALK5‐mediated Smad3 activation , 2006 .

[44]  Luzhe Sun,et al.  Transforming growth factor-beta suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation. , 2008, Cancer research.

[45]  Xu Cao,et al.  Endofin acts as a Smad anchor for receptor activation in BMP signaling , 2007, Journal of Cell Science.

[46]  D. Iliopoulos,et al.  E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. , 2008, Cancer cell.

[47]  C. Heldin,et al.  Notch signaling is necessary for epithelial growth arrest by TGF-β , 2007, The Journal of cell biology.

[48]  Xueli Yuan,et al.  Endothelial-to-mesenchymal transition contributes to cardiac fibrosis , 2007, Nature Medicine.

[49]  C. Heldin,et al.  Jcb: Report , 2022 .

[50]  H. Aburatani,et al.  Transforming growth factor-beta promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1. , 2007, Cancer research.

[51]  M. Korpal,et al.  The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2* , 2008, Journal of Biological Chemistry.

[52]  M. Bissell,et al.  Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo transforming growth factor beta induced epithelial to mesenchymal transition. , 2007, Cancer research.

[53]  C. Heldin,et al.  Non-Smad TGF-β signals , 2005, Journal of Cell Science.

[54]  J. Massagué,et al.  Smad transcription factors. , 2005, Genes & development.

[55]  Wei He,et al.  Hematopoiesis Controlled by Distinct TIF1γ and Smad4 Branches of the TGFβ Pathway , 2006, Cell.

[56]  C. Heldin,et al.  TGFβ1-Induced Activation of ATM and p53 Mediates Apoptosis in a Smad7-Dependent Manner , 2006, Cell cycle.

[57]  M. Yamashita,et al.  TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. , 2008, Molecular cell.

[58]  J. Hauser,et al.  Transforming growth factor beta induces apoptosis through repressing the phosphoinositide 3-kinase/AKT/survivin pathway in colon cancer cells. , 2008, Cancer research.

[59]  R. Kucherlapati,et al.  Deletion of Smad2 in Mouse Liver Reveals Novel Functions in Hepatocyte Growth and Differentiation , 2006, Molecular and Cellular Biology.

[60]  Y. Ip,et al.  Msk is required for nuclear import of TGF-β/BMP-activated Smads , 2007, The Journal of cell biology.

[61]  B. Hinz,et al.  Lkb1 is required for TGFβ-mediated myofibroblast differentiation , 2008, Journal of Cell Science.

[62]  H. Huber,et al.  PDGF essentially links TGF-β signaling to nuclear β-catenin accumulation in hepatocellular carcinoma progression , 2007, Oncogene.

[63]  C. Heldin,et al.  Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression , 2007, Cancer science.

[64]  Konstantinos J. Mavrakis,et al.  Arkadia Induces Degradation of SnoN and c-Ski to Enhance Transforming Growth Factor-β Signaling* , 2007, Journal of Biological Chemistry.

[65]  C. Heldin,et al.  Smad signal transduction : Smads in proliferation, differentiation and disease , 2006 .

[66]  Brian Bierie,et al.  Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer , 2006, Nature Reviews Cancer.

[67]  Tomoki Chiba,et al.  Smurf1 Interacts with Transforming Growth Factor-β Type I Receptor through Smad7 and Induces Receptor Degradation* , 2001, The Journal of Biological Chemistry.

[68]  Hui Wang,et al.  Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional suppression of transforming growth factor-beta receptor II. , 2008, Cancer research.

[69]  D. C. Clarke,et al.  Activation of Mps1 Promotes Transforming Growth Factor-β-independent Smad Signaling* , 2007, Journal of Biological Chemistry.

[70]  B. Olsen,et al.  Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. , 2008, Molecular biology of the cell.

[71]  C. Heldin,et al.  TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. , 2005, Molecular biology of the cell.

[72]  R. Bernards,et al.  Transforming Growth Factor-β Requires Its Target Plasminogen Activator Inhibitor-1 for Cytostatic Activity* , 2008, Journal of Biological Chemistry.

[73]  Alicia Zhou,et al.  Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers , 2007, Proceedings of the National Academy of Sciences.

[74]  Andrew J Link,et al.  A proximal activator of transcription in epithelial-mesenchymal transition. , 2007, The Journal of clinical investigation.

[75]  J. Wrana,et al.  Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. , 2000, Molecular cell.

[76]  S. Vukicevic,et al.  Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. , 2007, Cancer research.

[77]  M. Yaffe,et al.  TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal , 2008, Nature Cell Biology.

[78]  A. Hinck,et al.  Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. , 2008, Molecular cell.

[79]  C. Heldin,et al.  The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner , 2008, Nature Cell Biology.

[80]  Jean Paul Thiery,et al.  Epithelial-mesenchymal transitions in development and pathologies. , 2003, Current opinion in cell biology.

[81]  R. Derynck,et al.  SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS , 2005 .

[82]  U. Lendahl,et al.  Notch signaling mediates hypoxia-induced tumor cell migration and invasion , 2008, Proceedings of the National Academy of Sciences.

[83]  C. Heldin,et al.  Smad Signal Transduction , 2006 .

[84]  Y. Khew-Goodall,et al.  The protein tyrosine phosphatase Pez regulates TGFβ, epithelial–mesenchymal transition, and organ development , 2007, The Journal of cell biology.

[85]  K. Friedrich,et al.  Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor beta signaling. , 2008, Cancer research.

[86]  P. Dijke,et al.  Negative regulation of TGF-β receptor/Smad signal transduction , 2007 .

[87]  W. Kwiatkowski,et al.  The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. , 2003, Molecular cell.

[88]  C. Heldin,et al.  Id2 and Id3 Define the Potency of Cell Proliferation and Differentiation Responses to Transforming Growth Factor β and Bone Morphogenetic Protein , 2004, Molecular and Cellular Biology.

[89]  T. Morita,et al.  Dual roles of myocardin-related transcription factors in epithelial–mesenchymal transition via slug induction and actin remodeling , 2007, The Journal of cell biology.

[90]  T. Hunter,et al.  The Protein Kinase Complement of the Human Genome , 2002, Science.

[91]  A. Roberts,et al.  Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. , 1998, Genes & development.

[92]  Yue Zhang,et al.  Regulation of the Polarity Protein Par6 by TGFß Receptors Controls Epithelial Cell Plasticity , 2005, Science.

[93]  Héctor Peinado,et al.  Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? , 2007, Nature Reviews Cancer.

[94]  L. Alphey,et al.  PP1 binds Sara and negatively regulates Dpp signaling in Drosophila melanogaster , 2002, Nature Genetics.

[95]  J. Lasky,et al.  Requirement of HDAC6 for Transforming Growth Factor-β1-induced Epithelial-Mesenchymal Transition* , 2008, Journal of Biological Chemistry.

[96]  Xin-Hua Feng,et al.  Microtubule Binding to Smads May Regulate TGFβ Activity , 2000 .

[97]  Paul A. Bates,et al.  Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system , 2008, Proceedings of the National Academy of Sciences.

[98]  E. Guccione,et al.  A positive role for Myc in TGFβ-induced Snail transcription and epithelial-to-mesenchymal transition , 2009, Oncogene.

[99]  Zhi Wang,et al.  Endofin, a FYVE Domain Protein, Interacts with Smad4 and Facilitates Transforming Growth Factor-β Signaling* , 2007, Journal of Biological Chemistry.

[100]  Kohei Miyazono,et al.  Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells , 2008, Journal of Cell Science.

[101]  M. Jackson,et al.  Rb/E2F4 and Smad2/3 link survivin to TGF-β-induced apoptosis and tumor progression , 2008, Oncogene.

[102]  T. Sjöblom,et al.  Sustained TGFβ exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis , 2007, Oncogene.

[103]  A. Puisieux,et al.  Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition , 2008, PloS one.

[104]  R. Assoian,et al.  ABCG2 expression and side population abundance regulated by a transforming growth factor beta-directed epithelial-mesenchymal transition. , 2008, Cancer research.

[105]  William P Schiemann,et al.  Grb2 binding to Tyr284 in TbetaR-II is essential for mammary tumor growth and metastasis stimulated by TGF-beta. , 2008, Carcinogenesis.

[106]  Jing Qing,et al.  TGF‐β activates Erk MAP kinase signalling through direct phosphorylation of ShcA , 2007 .