Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Genes & Dev. 16 (15): 1950-1963

Copyright © 2002 by Cold Spring Harbor Laboratory Press.

Vol. 16, No. 15, pp. 1950-1963, August 1, 2002

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

Bin Y. Qin,1 Suvana S. Lam,1 John J. Correia,2 and Kai Lin1,3

1 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA; 2 Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA

Smad3 transduces the signals of TGF-beta s, 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.

[Key Words: TGF-beta ; Smad; phosphorylation; signaling; allosteric]


3 Corresponding author.


GENES & DEVELOPMENT 16:1950-1963 © 2002 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/02 $5.00


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Inhibition of TGF-{beta} Signaling at the Nuclear Envelope: Characterization of Interactions Between MAN1, Smad2 and Smad3, and PPM1A.
B. Bourgeois, B. Gilquin, C. Tellier-Lebegue, C. Ostlund, W. Wu, J. Perez, P. El Hage, F. Lallemand, H. J. Worman, and S. Zinn-Justin (2013)
Science Signaling 6, ra49
   Abstract »    Full Text »    PDF »
CCL2/CCR2 Chemokine Signaling Coordinates Survival and Motility of Breast Cancer Cells through Smad3 Protein- and p42/44 Mitogen-activated Protein Kinase (MAPK)-dependent Mechanisms.
W. B. Fang, I. Jokar, A. Zou, D. Lambert, P. Dendukuri, and N. Cheng (2012)
J. Biol. Chem. 287, 36593-36608
   Abstract »    Full Text »    PDF »
Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove.
A. Garai, A. Zeke, G. Gogl, I. Toro, F. Fordos, H. Blankenburg, T. Barkai, J. Varga, A. Alexa, D. Emig, et al. (2012)
Science Signaling 5, ra74
   Abstract »    Full Text »    PDF »
Expression, purification, and functional characterization of recombinant PTD-SARA.
C. Huang, R. Du, P. Zhang, H. Meng, H. Jia, Y. Song, M. Li, Y. Zhang, and S. Sun (2011)
Acta Biochim Biophys Sin 43, 110-117
   Abstract »    Full Text »    PDF »
Bone morphogenetic protein receptors and signal transduction.
K. Miyazono, Y. Kamiya, and M. Morikawa (2010)
J. Biochem. 147, 35-51
   Abstract »    Full Text »    PDF »
PCTA: A New Player in TGF-{beta} Signaling.
F. Liu (2008)
Science Signaling 1, pe49
   Abstract »    Full Text »    PDF »
Competition between Ski and CREB-binding Protein for Binding to Smad Proteins in Transforming Growth Factor-beta Signaling.
W. Chen, S. S. Lam, H. Srinath, C. A. Schiffer, W. E. Royer Jr., and K. Lin (2007)
J. Biol. Chem. 282, 11365-11376
   Abstract »    Full Text »    PDF »
Inhibition of Transforming Growth Factor-beta1-induced Signaling and Epithelial-to-Mesenchymal Transition by the Smad-binding Peptide Aptamer Trx-SARA.
B. M. Zhao and F. M. Hoffmann (2006)
Mol. Biol. Cell 17, 3819-3831
   Abstract »    Full Text »    PDF »
Characterization of a novel transcriptionally active domain in the transforming growth factor {beta}-regulated Smad3 protein.
V. Prokova, S. Mavridou, P. Papakosta, and D. Kardassis (2005)
Nucleic Acids Res. 33, 3708-3721
   Abstract »    Full Text »    PDF »
Nuclear Targeting of Transforming Growth Factor-{beta}-activated Smad Complexes.
H. B. Chen, J. G. Rud, K. Lin, and L. Xu (2005)
J. Biol. Chem. 280, 21329-21336
   Abstract »    Full Text »    PDF »
Transforming Growth Factor-{beta} Suppresses Nonmetastatic Colon Cancer through Smad4 and Adaptor Protein ELF at an Early Stage of Tumorigenesis.
Y. Tang, V. Katuri, R. Srinivasan, F. Fogt, R. Redman, G. Anand, A. Said, T. Fishbein, M. Zasloff, E. P. Reddy, et al. (2005)
Cancer Res. 65, 4228-4237
   Abstract »    Full Text »    PDF »
Transforming Growth Factor (TGF)-{beta}-activated Kinase 1 Mimics and Mediates TGF-{beta}-induced Stimulation of Type II Collagen Synthesis in Chondrocytes Independent of Col2a1 Transcription and Smad3 Signaling.
B. Qiao, S. R. Padilla, and P. D. Benya (2005)
J. Biol. Chem. 280, 17562-17571
   Abstract »    Full Text »    PDF »
A Direct Intersection between p53 and Transforming Growth Factor {beta} Pathways Targets Chromatin Modification and Transcription Repression of the {alpha}-Fetoprotein Gene.
D. S. Wilkinson, S. K. Ogden, S. A. Stratton, J. L. Piechan, T. T. Nguyen, G. A. Smulian, and M. C. Barton (2005)
Mol. Cell. Biol. 25, 1200-1212
   Abstract »    Full Text »    PDF »
Inhibin Resistance Is Associated with Aggressive Tumorigenicity of Ovarian Cancer Cells.
M. D. Steller, T. J. Shaw, B. C. Vanderhyden, and J.-F. Ethier (2005)
Mol. Cancer Res. 3, 50-61
   Abstract »    Full Text »    PDF »
Disorder in a Target for the Smad2 Mad Homology 2 Domain and Its Implications for Binding and Specificity.
P. A. Chong, B. Ozdamar, J. L. Wrana, and J. D. Forman-Kay (2004)
J. Biol. Chem. 279, 40707-40714
   Abstract »    Full Text »    PDF »
Repression of Endogenous Smad7 by Ski.
N. G. Denissova and F. Liu (2004)
J. Biol. Chem. 279, 28143-28148
   Abstract »    Full Text »    PDF »
Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski.
M. Takeda, M. Mizuide, M. Oka, T. Watabe, H. Inoue, H. Suzuki, T. Fujita, T. Imamura, K. Miyazono, and K. Miyazawa (2004)
Mol. Biol. Cell 15, 963-972
   Abstract »    Full Text »    PDF »
Recognition of Phosphorylated-Smad2-Containing Complexes by a Novel Smad Interaction Motif.
R. A. Randall, M. Howell, C. S. Page, A. Daly, P. A. Bates, and C. S. Hill (2004)
Mol. Cell. Biol. 24, 1106-1121
   Abstract »    Full Text »    PDF »
Distinct Domain Utilization by Smad3 and Smad4 for Nucleoporin Interaction and Nuclear Import.
L. Xu, C. Alarcon, S. Col, and J. Massague (2003)
J. Biol. Chem. 278, 42569-42577
   Abstract »    Full Text »    PDF »
Direct Interaction of Ski with Either Smad3 or Smad4 Is Necessary and Sufficient for Ski-mediated Repression of Transforming Growth Factor-{beta} Signaling.
N. Ueki and M. J. Hayman (2003)
J. Biol. Chem. 278, 32489-32492
   Abstract »    Full Text »    PDF »
The Transforming Activity of Ski and SnoN Is Dependent on Their Ability to Repress the Activity of Smad Proteins.
J. He, S. B. Tegen, A. R. Krawitz, G. S. Martin, and K. Luo (2003)
J. Biol. Chem. 278, 30540-30547
   Abstract »    Full Text »    PDF »
Uncoupling of Promitogenic and Antiapoptotic Functions of IL-2 by Smad-Dependent TGF-{beta} Signaling.
B. H. Nelson, T. P. Martyak, L. J. Thompson, J. J. Moon, and T. Wang (2003)
J. Immunol. 170, 5563-5570
   Abstract »    Full Text »    PDF »
Two Short Segments of Smad3 Are Important for Specific Interaction of Smad3 with c-Ski and SnoN.
M. Mizuide, T. Hara, T. Furuya, M. Takeda, K. Kusanagi, Y. Inada, M. Mori, T. Imamura, K. Miyazawa, and K. Miyazono (2003)
J. Biol. Chem. 278, 531-536
   Abstract »    Full Text »    PDF »
Stoichiometry of Active Smad-Transcription Factor Complexes on DNA.
G. J. Inman and C. S. Hill (2002)
J. Biol. Chem. 277, 51008-51016
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882