Home LiteratureArticle Details
PMID: 12154125 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control.

Genes & development ·Vol. 16 ·No. 15 ·2002-08-01 ·Pages 1950-63

Qin BY, Lam SS, Correia JJ, Lin K

Abstract

Smad3 transduces the signals of TGF-betas, coupling transmembrane receptor kinase activation to transcriptional control. The membrane-associated molecule SARA (Smad Anchor for Receptor Activation) recruits Smad3 for phosphorylation by the receptor kinase. Upon phosphorylation, Smad3 dissociates from SARA and enters the nucleus, in which its transcriptional activity can be repressed by Ski. Here, we show that SARA and Ski recognize specifically the monomeric and trimeric forms of Smad3, respectively. Thus, trimerization of Smad3, induced by phosphorylation, simultaneously activates the TGF-beta signal by driving Smad3 dissociation from SARA and sets up the negative feedback mechanism by Ski. Structural models of the Smad3/SARA/receptor kinase complex and Smad3/Ski complex provide insights into the molecular basis of regulation.

MeSH Terms
Allosteric Regulation Amino Acid Sequence Binding Sites Carrier Proteins/chemistry,physiology Crystallography, X-Ray DNA-Binding Proteins/chemistry,physiology Dimerization Enzyme Activation Humans Hydrophobic and Hydrophilic Interactions Intracellular Signaling Peptides and Proteins Macromolecular Substances Models, Molecular Molecular Sequence Data Phosphorylation Protein Conformation Protein Interaction Mapping Protein Processing, Post-Translational Protein Serine-Threonine Kinases/chemistry,physiology Protein Structure, Tertiary Proto-Oncogene Proteins/chemistry,physiology Receptor, Transforming Growth Factor-beta Type I Receptors, Transforming Growth Factor beta Serine Endopeptidases Smad3 Protein Trans-Activators/chemistry,physiology Transcription, Genetic/physiology
Chemicals
Carrier Proteins DNA-Binding Proteins Intracellular Signaling Peptides and Proteins Macromolecular Substances Proto-Oncogene Proteins Receptors, Transforming Growth Factor beta SMAD3 protein, human Smad3 Protein Trans-Activators SKI protein, human Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type I ZFYVE16 protein, human Serine Endopeptidases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Qin Bin Y
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Lam Suvana S
Correia John J
Lin Kai
References (48)
48 references, click to expand
  1. Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12.
    Cell. 1999 Feb 5;96(3):425-36 PMID: 10025408
  2. The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling.
    Genes Dev. 1999 Sep 1;13(17):2196-206 PMID: 10485843
  3. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling.
    Mol Cell. 1999 Oct;4(4):499-509 PMID: 10549282
  4. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads.
    J Biol Chem. 1999 Dec 3;274(49):35269-77 PMID: 10575014
  5. TGF-beta signaling from receptors to the nucleus.
    Microbes Infect. 1999 Dec;1(15):1265-73 PMID: 10611754
  6. Structural basis of Smad2 recognition by the Smad anchor for receptor activation.
    Science. 2000 Jan 7;287(5450):92-7 PMID: 10615055
  7. The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain.
    J Biol Chem. 2000 Jan 21;275(3):2115-22 PMID: 10636916
  8. Crystal structure of a transcriptionally active Smad4 fragment.
    Structure. 1999 Dec 15;7(12):1493-503 PMID: 10647180
  9. A method for directly fitting the time derivative of sedimentation velocity data and an alternative algorithm for calculating sedimentation coefficient distribution functions.
    Anal Biochem. 2000 Mar 15;279(2):151-63 PMID: 10706784
  10. Smads as transcriptional co-modulators.
    Curr Opin Cell Biol. 2000 Apr;12(2):235-43 PMID: 10712925
  11. Transcriptional control by the TGF-beta/Smad signaling system.
    EMBO J. 2000 Apr 17;19(8):1745-54 PMID: 10775259
  12. Role of transforming growth factor beta in human disease.
    N Engl J Med. 2000 May 4;342(18):1350-8 PMID: 10793168
  13. Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor.
    Proc Natl Acad Sci U S A. 2000 May 23;97(11):5924-9 PMID: 10811875
  14. Crystal structure of the BMP-2-BRIA ectodomain complex.
    Nat Struct Biol. 2000 Jun;7(6):492-6 PMID: 10881198
  15. Role of transforming growth factor-beta signaling in cancer.
    J Natl Cancer Inst. 2000 Sep 6;92(17):1388-402 PMID: 10974075
  16. Distinct oligomeric states of SMAD proteins in the transforming growth factor-beta pathway.
    J Biol Chem. 2000 Dec 29;275(52):40710-7 PMID: 11018029
  17. Sedimentation studies reveal a direct role of phosphorylation in Smad3:Smad4 homo- and hetero-trimerization.
    Biochemistry. 2001 Feb 6;40(5):1473-82 PMID: 11170475
  18. The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization.
    Nat Struct Biol. 2001 Mar;8(3):248-53 PMID: 11224571
  19. Ski/Sno and TGF-beta signaling.
    Cytokine Growth Factor Rev. 2001 Mar;12(1):1-8 PMID: 11312113
  20. The TGF beta receptor activation process: an inhibitor- to substrate-binding switch.
    Mol Cell. 2001 Sep;8(3):671-82 PMID: 11583628
  21. Multivalent endosome targeting by homodimeric EEA1.
    Mol Cell. 2001 Nov;8(5):947-58 PMID: 11741531
  22. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.
    Mol Cell. 2001 Dec;8(6):1277-89 PMID: 11779503
  23. Structural basis of Smad1 activation by receptor kinase phosphorylation.
    Mol Cell. 2001 Dec;8(6):1303-12 PMID: 11779505
  24. Different Smad2 partners bind a common hydrophobic pocket in Smad2 via a defined proline-rich motif.
    EMBO J. 2002 Jan 15;21(1-2):145-56 PMID: 11782434
  25. Phosphoserine-dependent regulation of protein-protein interactions in the Smad pathway.
    Structure. 2002 Jan;10(1):5-7 PMID: 11796104
  26. Crystal structure of the human TbetaR2 ectodomain--TGF-beta3 complex.
    Nat Struct Biol. 2002 Mar;9(3):203-8 PMID: 11850637
  27. Processing of X-ray diffraction data collected in oscillation mode.
    Methods Enzymol. 1997;276:307-26 PMID: 27754618
  28. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex.
    EMBO J. 1995 May 15;14(10):2199-208 PMID: 7774578
  29. Mechanism of activation of the TGF-beta receptor.
    Nature. 1994 Aug 4;370(6488):341-7 PMID: 8047140
  30. The specificity of the transforming growth factor beta receptor kinases determined by a spatially addressable peptide library.
    Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11761-5 PMID: 8524844
  31. Formation and activation by phosphorylation of activin receptor complexes.
    Mol Endocrinol. 1996 Apr;10(4):367-79 PMID: 8721982
  32. Signaling by chimeric erythropoietin-TGF-beta receptors: homodimerization of the cytoplasmic domain of the type I TGF-beta receptor and heterodimerization with the type II receptor are both required for intracellular signal transduction.
    EMBO J. 1996 Sep 2;15(17):4485-96 PMID: 8887540
  33. MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling.
    Cell. 1996 Dec 27;87(7):1215-24 PMID: 8980228
  34. An improved function for fitting sedimentation velocity data for low-molecular-weight solutes.
    Biophys J. 1997 Jan;72(1):435-44 PMID: 8994630
  35. Characterization of functional domains within Smad4/DPC4.
    J Biol Chem. 1997 May 23;272(21):13690-6 PMID: 9153220
  36. A structural basis for mutational inactivation of the tumour suppressor Smad4.
    Nature. 1997 Jul 3;388(6637):87-93 PMID: 9214508
  37. A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity.
    EMBO J. 1997 Jul 1;16(13):3912-23 PMID: 9233801
  38. TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling.
    J Biol Chem. 1997 Oct 31;272(44):27678-85 PMID: 9346908
  39. Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling.
    J Biol Chem. 1997 Oct 31;272(44):28107-15 PMID: 9346966
  40. TGF-beta signalling from cell membrane to nucleus through SMAD proteins.
    Nature. 1997 Dec 4;390(6659):465-71 PMID: 9393997
  41. The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-beta receptors.
    EMBO J. 1998 Feb 16;17(4):996-1005 PMID: 9463378
  42. Oligomeric structure of type I and type II transforming growth factor beta receptors: homodimers form in the ER and persist at the plasma membrane.
    J Cell Biol. 1998 Feb 23;140(4):767-77 PMID: 9472030
  43. Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors.
    EMBO J. 1998 Jul 15;17(14):4056-65 PMID: 9670020
  44. Determinants of specificity in TGF-beta signal transduction.
    Genes Dev. 1998 Jul 15;12(14):2144-52 PMID: 9679059
  45. The L45 loop in type I receptors for TGF-beta family members is a critical determinant in specifying Smad isoform activation.
    FEBS Lett. 1998 Aug 28;434(1-2):83-7 PMID: 9738456
  46. Crystallography & NMR system: A new software suite for macromolecular structure determination.
    Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21 PMID: 9757107
  47. Smads: transcriptional activators of TGF-beta responses.
    Cell. 1998 Dec 11;95(6):737-40 PMID: 9865691
  48. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor.
    Cell. 1998 Dec 11;95(6):779-91 PMID: 9865696
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1002002
Published
2002-08-01
Pages
1950-63
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC186427
Subset
IM
Corrections
CommentIn
PMID: 12154118
External Links
PubMed source DOI: 10.1101/gad.1002002 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2