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PDBsum entry 1ygs

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Tumour suppressor PDB id
1ygs
Jmol
Contents
Protein chain
190 a.a. *
Waters ×138
* Residue conservation analysis
PDB id:
1ygs
Name: Tumour suppressor
Title: Crystal structure of the smad4 tumor suppressor c-terminal domain
Structure: Smad4. Chain: a. Fragment: c-terminal domain, residues 319 - 552. Synonym: dpc4, hmad4, madr4. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21 (de3). Cellular_location: cytoplasm (can be translocated into nucleus). Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell_line: bl21 (de3).
Biol. unit: Trimer (from PQS)
Resolution:
2.10Å     R-factor:   0.219     R-free:   0.279
Authors: Y.Shi,A.Hata,R.S.Lo,J.Massague,N.P.Pavletich
Key ref:
Y.Shi et al. (1997). A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature, 388, 87-93. PubMed id: 9214508 DOI: 10.1038/40431
Date:
03-Oct-97     Release date:   08-Jul-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q13485  (SMAD4_HUMAN) -  Mothers against decapentaplegic homolog 4
Seq:
Struc:
 
Seq:
Struc:
552 a.a.
190 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   1 term 
  Biological process     regulation of transcription, DNA-dependent   1 term 

 

 
DOI no: 10.1038/40431 Nature 388:87-93 (1997)
PubMed id: 9214508  
 
 
A structural basis for mutational inactivation of the tumour suppressor Smad4.
Y.Shi, A.Hata, R.S.Lo, J.Massagué, N.P.Pavletich.
 
  ABSTRACT  
 
The Smad4/DPC4 tumour suppressor is inactivated in nearly half of pancreatic carcinomas and to a lesser extent in a variety of other cancers. Smad4/DPC4, and the related tumour suppressor Smad2, belong to the SMAD family of proteins that mediate signalling by the TGF-beta/activin/BMP-2/4 cytokine superfamily from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins, which are phosphorylated by the activated receptor, propagate the signal, in part, through homo- and hetero-oligomeric interactions. Smad4/DPC4 plays a central role as it is the shared hetero-oligomerization partner of the other SMADs. The conserved carboxy-terminal domains of SMADs are sufficient for inducing most of the ligand-specific effects, and are the primary targets of tumorigenic inactivation. We now describe the crystal structure of the C-terminal domain (CTD) of the Smad4/DPC4 tumour suppressor, determined at 2.5 A resolution. The structure reveals that the Smad4/DPC4 CTD forms a crystallographic trimer through a conserved protein-protein interface, to which the majority of the tumour-derived missense mutations map. These mutations disrupt homo-oligomerization in vitro and in vivo, indicating that the trimeric assembly of the Smad4/DPC4 CTD is critical for signalling and is disrupted by tumorigenic mutations.
 
  Selected figure(s)  
 
Figure 1.
Figure 1 The structure of the Smad4/DPC4 CTD consists of a -sandwich with a three-helix bundle on one end and a collection of three large loops and an -helix on the other. The view is along the edge of the -sandwich; the dotted line represents the disordered region between the H3 and H4 helices. Figures were prepared with the programs MOLSCRIPT26 and RASTER3D^27.
Figure 5.
Figure 5 One face of the disk-like trimer structure may mediate hetero-oligomerization. a, Mutations outside the trimer interface map primarily to L3-loop residues, with the exception of Arg 420, which is outside the L3 loop. The face of the trimer shown is opposite to that shown in Fig. 3a. b, Model of hetero-oligomer formation depicting the Smad4/DPC4 and Smad2 CTD trimers as disks. The approximate positions of the Smad4/DPC4 L3 loops and of the Smad2 sites that get phosphorylated by the receptor kinase^30 are shown in yellow and green, respectively.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1997, 388, 87-93) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19762341 K.Miyazono, Y.Kamiya, and M.Morikawa (2010).
Bone morphogenetic protein receptors and signal transduction.
  J Biochem, 147, 35-51.  
21145485 L.Huang, A.Serganov, and D.J.Patel (2010).
Structural insights into ligand recognition by a sensing domain of the cooperative glycine riboswitch.
  Mol Cell, 40, 774-786.
PDB codes: 3owi 3oww 3owz 3ox0 3oxb 3oxd 3oxe 3oxj 3oxm
20308189 N.G.Brown, and T.Palzkill (2010).
Identification and characterization of beta-lactamase inhibitor protein-II (BLIP-II) interactions with beta-lactamases using phage display.
  Protein Eng Des Sel, 23, 469-478.  
20923499 S.N.Yang, M.L.Burch, L.R.Tannock, S.Evanko, N.Osman, and P.J.Little (2010).
Transforming growth factor-β regulation of proteoglycan synthesis in vascular smooth muscle: contribution to lipid binding and accelerated atherosclerosis in diabetes.
  J Diabetes, 2, 233-242.  
20148926 S.Tao, and K.Sampath (2010).
Alternative splicing of SMADs in differentiation and tissue homeostasis.
  Dev Growth Differ, 52, 335-342.  
19690946 Y.Shi, K.Ye, H.Wu, Y.Sun, H.Shi, and K.Huo (2010).
Human SMAD4 is phosphorylated at Thr9 and Ser138 by interacting with NLK.
  Mol Cell Biochem, 333, 293-298.  
19557331 C.Wang, L.Chen, L.Wang, and J.Wu (2009).
Crystal structure of the MH2 domain of Drosophila Mad.
  Sci China C Life Sci, 52, 539-544.
PDB code: 3gmj
  18997322 R.Hao, L.Chen, J.W.Wu, and Z.X.Wang (2008).
Structure of Drosophila Mad MH2 domain.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 986-990.
PDB code: 3dit
18061509 S.Ross, and C.S.Hill (2008).
How the Smads regulate transcription.
  Int J Biochem Cell Biol, 40, 383-408.  
16904831 K.Pardali, and A.Moustakas (2007).
Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer.
  Biochim Biophys Acta, 1775, 21-62.  
16449645 A.Kurisaki, K.Kurisaki, M.Kowanetz, H.Sugino, Y.Yoneda, C.H.Heldin, and A.Moustakas (2006).
The mechanism of nuclear export of Smad3 involves exportin 4 and Ran.
  Mol Cell Biol, 26, 1318-1332.  
16433931 H.T.Chang, T.W.Pai, T.C.Fan, B.H.Su, P.C.Wu, C.Y.Tang, C.T.Chang, S.H.Liu, and M.D.Chang (2006).
A reinforced merging methodology for mapping unique peptide motifs in members of protein families.
  BMC Bioinformatics, 7, 38.  
16865698 L.Yang, N.Wang, Y.Tang, X.Cao, and M.Wan (2006).
Acute myelogenous leukemia-derived SMAD4 mutations target the protein to ubiquitin-proteasome degradation.
  Hum Mutat, 27, 897-905.  
16829514 S.Gao, and A.Laughon (2006).
Decapentaplegic-responsive silencers contain overlapping mad-binding sites.
  J Biol Chem, 281, 25781-25790.  
17132729 S.K.Lim, and F.M.Hoffmann (2006).
Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF-beta signaling.
  Proc Natl Acad Sci U S A, 103, 18580-18585.  
16518688 Y.Chen, D.Yee, and T.Magnuson (2006).
A novel mouse Smad4 mutation reduces protein stability and wild-type protein levels.
  Mamm Genome, 17, 211-219.  
15817471 A.Morén, T.Imamura, K.Miyazono, C.H.Heldin, and A.Moustakas (2005).
Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases.
  J Biol Chem, 280, 22115-22123.  
15940269 D.Lazzereschi, F.Nardi, A.Turco, L.Ottini, C.D'Amico, R.Mariani-Costantini, A.Gulino, and A.Coppa (2005).
A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours.
  Oncogene, 24, 5344-5354.  
  15855639 M.Wan, J.Huang, N.C.Jhala, E.M.Tytler, L.Yang, S.M.Vickers, Y.Tang, C.Lu, N.Wang, and X.Cao (2005).
SCF(beta-TrCP1) controls Smad4 protein stability in pancreatic cancer cells.
  Am J Pathol, 166, 1379-1392.  
16314499 Q.Zhu, S.Pearson-White, and K.Luo (2005).
Requirement for the SnoN oncoprotein in transforming growth factor beta-induced oncogenic transformation of fibroblast cells.
  Mol Cell Biol, 25, 10731-10744.  
16109720 S.Gao, J.Steffen, and A.Laughon (2005).
Dpp-responsive silencers are bound by a trimeric Mad-Medea complex.
  J Biol Chem, 280, 36158-36164.  
  16511117 V.Oganesyan, C.Huang, P.D.Adams, J.Jancarik, H.A.Yokota, R.Kim, and S.H.Kim (2005).
Structure of a NAD kinase from Thermotoga maritima at 2.3 A resolution.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 640-646.
PDB code: 1yt5
15994459 V.Prokova, S.Mavridou, P.Papakosta, and D.Kardassis (2005).
Characterization of a novel transcriptionally active domain in the transforming growth factor beta-regulated Smad3 protein.
  Nucleic Acids Res, 33, 3708-3721.  
15705182 W.Wang, V.Koka, and H.Y.Lan (2005).
Transforming growth factor-beta and Smad signalling in kidney diseases.
  Nephrology (Carlton), 10, 48-56.  
16212511 X.H.Feng, and R.Derynck (2005).
Specificity and versatility in tgf-beta signaling through Smads.
  Annu Rev Cell Dev Biol, 21, 659-693.  
15264272 A.Merg, and J.R.Howe (2004).
Genetic conditions associated with intestinal juvenile polyps.
  Am J Med Genet C Semin Med Genet, 129, 44-55.  
15031030 C.J.Gallione, G.M.Repetto, E.Legius, A.K.Rustgi, S.L.Schelley, S.Tejpar, G.Mitchell, E.Drouin, C.J.Westermann, and D.A.Marchuk (2004).
A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).
  Lancet, 363, 852-859.  
15210694 I.Yakymovych, C.H.Heldin, and S.Souchelnytskyi (2004).
Smad2 phosphorylation by type I receptor: contribution of arginine 462 and cysteine 463 In the C terminus of Smad2 for specificity.
  J Biol Chem, 279, 35781-35787.  
14729983 J.Qing, C.Liu, L.Choy, R.Y.Wu, J.S.Pagano, and R.Derynck (2004).
Transforming growth factor beta/Smad3 signaling regulates IRF-7 function and transcriptional activation of the beta interferon promoter.
  Mol Cell Biol, 24, 1411-1425.  
15235019 J.R.Howe, M.G.Sayed, A.F.Ahmed, J.Ringold, J.Larsen-Haidle, A.Merg, F.A.Mitros, C.A.Vaccaro, G.M.Petersen, F.M.Giardiello, S.T.Tinley, L.A.Aaltonen, and H.T.Lynch (2004).
The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.
  J Med Genet, 41, 484-491.  
15318814 J.Springer, F.R.Scholz, C.Peiser, D.A.Groneberg, and A.Fischer (2004).
SMAD-signaling in chronic obstructive pulmonary disease: transcriptional down-regulation of inhibitory SMAD 6 and 7 by cigarette smoke.
  Biol Chem, 385, 649-653.  
14720321 M.Kondo, H.Suzuki, K.Takehara, K.Miyazono, and M.Kato (2004).
Transforming growth factor-beta signaling is differentially inhibited by Smad2D450E and Smad3D407E.
  Cancer Sci, 95, 12-17.  
14729957 R.A.Randall, M.Howell, C.S.Page, A.Daly, P.A.Bates, and C.S.Hill (2004).
Recognition of phosphorylated-Smad2-containing complexes by a novel Smad interaction motif.
  Mol Cell Biol, 24, 1106-1121.  
15312649 S.Atanasoski, L.Notterpek, H.Y.Lee, F.Castagner, P.Young, M.U.Ehrengruber, D.Meijer, L.Sommer, E.Stavnezer, C.Colmenares, and U.Suter (2004).
The protooncogene Ski controls Schwann cell proliferation and myelination.
  Neuron, 43, 499-511.  
15148321 T.Mochizuki, H.Miyazaki, T.Hara, T.Furuya, T.Imamura, T.Watabe, and K.Miyazono (2004).
Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-beta superfamily signaling.
  J Biol Chem, 279, 31568-31574.  
12551947 A.V.Grinberg, and T.Kerppola (2003).
Both Max and TFE3 cooperate with Smad proteins to bind the plasminogen activator inhibitor-1 promoter, but they have opposite effects on transcriptional activity.
  J Biol Chem, 278, 11227-11236.  
14526373 K.A.Waite, and C.Eng (2003).
From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family.
  Nat Rev Genet, 4, 763-773.  
14555995 K.Takahasi, N.N.Suzuki, M.Horiuchi, M.Mori, W.Suhara, Y.Okabe, Y.Fukuhara, H.Terasawa, S.Akira, T.Fujita, and F.Inagaki (2003).
X-ray crystal structure of IRF-3 and its functional implications.
  Nat Struct Biol, 10, 922-927.
PDB code: 1j2f
12440701 A.Mehra, and J.L.Wrana (2002).
TGF-beta and the Smad signal transduction pathway.
  Biochem Cell Biol, 80, 605-622.  
12116240 B.Burger, S.Uhlhaas, E.Mangold, P.Propping, W.Friedl, D.Jenne, G.Dockter, and W.Back (2002).
Novel de novo mutation of MADH4/SMAD4 in a patient with juvenile polyposis.
  Am J Med Genet, 110, 289-291.  
12154125 B.Y.Qin, S.S.Lam, J.J.Correia, and K.Lin (2002).
Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control.
  Genes Dev, 16, 1950-1963.
PDB codes: 1mjs 1mk2
12097320 D.K.Lee, B.C.Kim, J.N.Brady, K.T.Jeang, and S.J.Kim (2002).
Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-beta signaling by blocking the association of Smad proteins with Smad-binding element.
  J Biol Chem, 277, 33766-33775.  
11818142 D.U.Kloos, C.Choi, and E.Wingender (2002).
The TGF-beta--Smad network: introducing bioinformatic tools.
  Trends Genet, 18, 96.  
11841535 F.Verrecchia, and A.Mauviel (2002).
Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation.
  J Invest Dermatol, 118, 211-215.  
12374795 G.J.Inman, and C.S.Hill (2002).
Stoichiometry of active smad-transcription factor complexes on DNA.
  J Biol Chem, 277, 51008-51016.  
12410091 H.Ihn (2002).
Pathogenesis of fibrosis: role of TGF-beta and CTGF.
  Curr Opin Rheumatol, 14, 681-685.  
12432092 J.L.Vivian, Y.Chen, D.Yee, E.Schneider, and T.Magnuson (2002).
An allelic series of mutations in Smad2 and Smad4 identified in a genotype-based screen of N-ethyl-N- nitrosourea-mutagenized mouse embryonic stem cells.
  Proc Natl Acad Sci U S A, 99, 15542-15547.  
12419246 J.W.Wu, A.R.Krawitz, J.Chai, W.Li, F.Zhang, K.Luo, and Y.Shi (2002).
Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-beta signaling.
  Cell, 111, 357-367.
PDB code: 1mr1
12012345 M.A.Huntley, and G.B.Golding (2002).
Simple sequences are rare in the Protein Data Bank.
  Proteins, 48, 134-140.  
12417513 M.G.Sayed, A.F.Ahmed, J.R.Ringold, M.E.Anderson, J.L.Bair, F.A.Mitros, H.T.Lynch, S.T.Tinley, G.M.Petersen, F.M.Giardiello, B.Vogelstein, and J.R.Howe (2002).
Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis.
  Ann Surg Oncol, 9, 901-906.  
11920677 P.Ten Dijke, M.J.Goumans, F.Itoh, and S.Itoh (2002).
Regulation of cell proliferation by Smad proteins.
  J Cell Physiol, 191, 1.  
11782434 R.A.Randall, S.Germain, G.J.Inman, P.A.Bates, and C.S.Hill (2002).
Different Smad2 partners bind a common hydrophobic pocket in Smad2 via a defined proline-rich motif.
  EMBO J, 21, 145-156.  
12077092 R.Salovaara, S.Roth, A.Loukola, V.Launonen, P.Sistonen, E.Avizienyte, P.Kristo, H.Järvinen, S.Souchelnytskyi, M.Sarlomo-Rikala, and L.A.Aaltonen (2002).
Frequent loss of SMAD4/DPC4 protein in colorectal cancers.
  Gut, 51, 56-59.  
  11294908 A.Kurisaki, S.Kose, Y.Yoneda, C.H.Heldin, and A.Moustakas (2001).
Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner.
  Mol Biol Cell, 12, 1079-1091.  
11779505 B.Y.Qin, B.M.Chacko, S.S.Lam, M.P.de Caestecker, J.J.Correia, and K.Lin (2001).
Structural basis of Smad1 activation by receptor kinase phosphorylation.
  Mol Cell, 8, 1303-1312.
PDB code: 1khu
11313456 C.Prunier, N.Ferrand, B.Frottier, M.Pessah, and A.Atfi (2001).
Mechanism for mutational inactivation of the tumor suppressor Smad2.
  Mol Cell Biol, 21, 3302-3313.  
11553622 D.Maurice, C.E.Pierreux, M.Howell, R.E.Wilentz, M.J.Owen, and C.S.Hill (2001).
Loss of Smad4 function in pancreatic tumors: C-terminal truncation leads to decreased stability.
  J Biol Chem, 276, 43175-43181.  
11478521 G.Samuel, D.Miller, and R.Saint (2001).
Conservation of a DPP/BMP signaling pathway in the nonbilateral cnidarian Acropora millepora.
  Evol Dev, 3, 241-250.  
11170475 J.J.Correia, B.M.Chacko, S.S.Lam, and K.Lin (2001).
Sedimentation studies reveal a direct role of phosphorylation in Smad3:Smad4 homo- and hetero-trimerization.
  Biochemistry, 40, 1473-1482.  
11779503 J.W.Wu, M.Hu, J.Chai, J.Seoane, M.Huse, C.Li, D.J.Rigotti, S.Kyin, T.W.Muir, R.Fairman, J.Massagué, and Y.Shi (2001).
Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.
  Mol Cell, 8, 1277-1289.
PDB code: 1khx
11481457 K.L.Woodford-Richens, A.J.Rowan, P.Gorman, S.Halford, D.C.Bicknell, H.S.Wasan, R.R.Roylance, W.F.Bodmer, and I.P.Tomlinson (2001).
SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway.
  Proc Natl Acad Sci U S A, 98, 9719-9723.  
  11583957 K.L.Woodford-Richens, A.J.Rowan, R.Poulsom, S.Bevan, R.Salovaara, L.A.Aaltonen, R.S.Houlston, N.A.Wright, and I.P.Tomlinson (2001).
Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers.
  Am J Pathol, 159, 1293-1300.  
  11532220 L.Attisano, and S.Tuen Lee-Hoeflich (2001).
The Smads.
  Genome Biol, 2, REVIEWS3010.  
11148690 R.Wieser (2001).
The transforming growth factor-beta signaling pathway in tumorigenesis.
  Curr Opin Oncol, 13, 70-77.  
11555647 T.Matsuda, T.Yamamoto, A.Muraguchi, and F.Saatcioglu (2001).
Cross-talk between transforming growth factor-beta and estrogen receptor signaling through Smad3.
  J Biol Chem, 276, 42908-42914.  
11170301 X.J.Wang (2001).
Role of TGFbeta signaling in skin carcinogenesis.
  Microsc Res Tech, 52, 420-429.  
11223879 Y.Shi (2001).
Structural insights on Smad function in TGFbeta signaling.
  Bioessays, 23, 223-232.  
11509558 Z.Xiao, N.Watson, C.Rodriguez, and H.F.Lodish (2001).
Nucleocytoplasmic shuttling of Smad1 conferred by its nuclear localization and nuclear export signals.
  J Biol Chem, 276, 39404-39410.  
10918299 D.J.Phillips (2000).
Regulation of activin's access to the cell: why is mother nature such a control freak?
  Bioessays, 22, 689-696.  
10615055 G.Wu, Y.G.Chen, B.Ozdamar, C.A.Gyuricza, P.A.Chong, J.L.Wrana, J.Massagué, and Y.Shi (2000).
Structural basis of Smad2 recognition by the Smad anchor for receptor activation.
  Science, 287, 92-97.
PDB code: 1dev
10871368 J.B.Jones, and S.E.Kern (2000).
Functional mapping of the MH1 DNA-binding domain of DPC4/SMAD4.
  Nucleic Acids Res, 28, 2363-2368.  
10708948 J.L.Wrana, and L.Attisano (2000).
The Smad pathway.
  Cytokine Growth Factor Rev, 11, 5.  
10775259 J.Massagué, and D.Wotton (2000).
Transcriptional control by the TGF-beta/Smad signaling system.
  EMBO J, 19, 1745-1754.  
11057902 J.Massagué, S.W.Blain, and R.S.Lo (2000).
TGFbeta signaling in growth control, cancer, and heritable disorders.
  Cell, 103, 295-309.  
10781087 J.Xu, and L.Attisano (2000).
Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway.
  Proc Natl Acad Sci U S A, 97, 4820-4825.  
10712925 L.Attisano, and J.L.Wrana (2000).
Smads as transcriptional co-modulators.
  Curr Opin Cell Biol, 12, 235-243.  
10636916 M.P.de Caestecker, T.Yahata, D.Wang, W.T.Parks, S.Huang, C.S.Hill, T.Shioda, A.B.Roberts, and R.J.Lechleider (2000).
The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain.
  J Biol Chem, 275, 2115-2122.  
11265759 M.Watanabe, N.Masuyama, M.Fukuda, and E.Nishida (2000).
Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal.
  EMBO Rep, 1, 176-182.  
10823886 N.G.Denissova, C.Pouponnot, J.Long, D.He, and F.Liu (2000).
Transforming growth factor beta -inducible independent binding of SMAD to the Smad7 promoter.
  Proc Natl Acad Sci U S A, 97, 6397-6402.  
  10887155 R.H.Kim, D.Wang, M.Tsang, J.Martin, C.Huff, M.P.de Caestecker, W.T.Parks, X.Meng, R.J.Lechleider, T.Wang, and A.B.Roberts (2000).
A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction.
  Genes Dev, 14, 1605-1616.  
10564585 R.H.Zurawel, C.Allen, S.Chiappa, W.Cato, J.Biegel, P.Cogen, F.de Sauvage, and C.Raffel (2000).
Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma.
  Genes Chromosomes Cancer, 27, 44-51.  
11013220 X.H.Feng, X.Lin, and R.Derynck (2000).
Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta.
  EMBO J, 19, 5178-5193.  
10420150 A.Latil, S.Pesche, A.Valéri, G.Fournier, O.Cussenot, and R.Lidereau (1999).
Expression and mutational analysis of the MADR2/Smad2 gene in human prostate cancer.
  Prostate, 40, 225-231.  
10647180 B.Qin, S.S.Lam, and K.Lin (1999).
Crystal structure of a transcriptionally active Smad4 fragment.
  Structure, 7, 1493-1503.
PDB code: 1dd1
10605817 C.S.Hill (1999).
The Smads.
  Int J Biochem Cell Biol, 31, 1249-1254.  
10199400 D.Wotton, R.S.Lo, S.Lee, and J.Massagué (1999).
A Smad transcriptional corepressor.
  Cell, 97, 29-39.  
10090153 G.Lagna, and A.Hemmati-Brivanlou (1999).
A molecular basis for Smad specificity.
  Dev Dyn, 214, 269-277.  
10376010 J.L.Christian, and T.Nakayama (1999).
Can't get no SMADisfaction: Smad proteins as positive and negative regulators of TGF-beta family signals.
  Bioessays, 21, 382-390.  
9990040 J.L.Dai, R.K.Bansal, and S.E.Kern (1999).
G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: phenotypes reversed by a tumorigenic mutation.
  Proc Natl Acad Sci U S A, 96, 1427-1432.  
10400705 K.Johnson, H.Kirkpatrick, A.Comer, F.M.Hoffmann, and A.Laughon (1999).
Interaction of Smad complexes with tripartite DNA-binding sites.
  J Biol Chem, 274, 20709-20716.  
10673036 K.L.Pearson, T.Hunter, and R.Janknecht (1999).
Activation of Smad1-mediated transcription by p300/CBP.
  Biochim Biophys Acta, 1489, 354-364.  
10485843 K.Luo, S.L.Stroschein, W.Wang, D.Chen, E.Martens, S.Zhou, and Q.Zhou (1999).
The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling.
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10620018 K.Tada, H.Inoue, T.Ebisawa, M.Makuuchi, M.Kawabata, T.Imamura, and K.Miyazono (1999).
Region between alpha-helices 3 and 4 of the mad homology 2 domain of Smad4: functional roles in oligomer formation and transcriptional activation.
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A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras.
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10207044 N.Masuyama, H.Hanafusa, M.Kusakabe, H.Shibuya, and E.Nishida (1999).
Identification of two Smad4 proteins in Xenopus. Their common and distinct properties.
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10531318 R.P.Nagarajan, J.Liu, and Y.Chen (1999).
Smad3 inhibits transforming growth factor-beta and activin signaling by competing with Smad4 for FAST-2 binding.
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10092624 S.L.Stroschein, W.Wang, and K.Luo (1999).
Cooperative binding of Smad proteins to two adjacent DNA elements in the plasminogen activator inhibitor-1 promoter mediates transforming growth factor beta-induced smad-dependent transcriptional activation.
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10531062 S.L.Stroschein, W.Wang, S.Zhou, Q.Zhou, and K.Luo (1999).
Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein.
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10451707 S.Takakura, A.Okamoto, M.Saito, T.Yasuhara, H.Shinozaki, S.Isonishi, T.Yoshimura, Y.Ohtake, K.Ochiai, and T.Tanaka (1999).
Allelic imbalance in chromosome band 18q21 and SMAD4 mutations in ovarian cancers.
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9892110 T.Jonson, L.Gorunova, S.Dawiskiba, A.Andrén-Sandberg, G.Stenman, P.ten Dijke, B.Johansson, and M.Höglund (1999).
Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer.
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10440999 W.Hilgers, and S.E.Kern (1999).
Molecular genetic basis of pancreatic adenocarcinoma.
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9920917 Y.G.Chen, and J.Massagué (1999).
Smad1 recognition and activation by the ALK1 group of transforming growth factor-beta family receptors.
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10370243 Y.Zhang, and R.Derynck (1999).
Regulation of Smad signalling by protein associations and signalling crosstalk.
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Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor.
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Physical and functional interaction of SMADs and p300/CBP.
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  9420335 C.Sirard, J.L.de la Pompa, A.Elia, A.Itie, C.Mirtsos, A.Cheung, S.Hahn, A.Wakeham, L.Schwartz, S.E.Kern, J.Rossant, and T.W.Mak (1998).
The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo.
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9792626 C.Z.Song, T.E.Siok, and T.D.Gelehrter (1998).
Smad4/DPC4 and Smad3 mediate transforming growth factor-beta (TGF-beta) signaling through direct binding to a novel TGF-beta-responsive element in the human plasminogen activator inhibitor-1 promoter.
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Smad4 (DPC4)--a potent tumour suppressor?
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  9693372 H.Inoue, T.Imamura, Y.Ishidou, M.Takase, Y.Udagawa, Y.Oka, K.Tsuneizumi, T.Tabata, K.Miyazono, and M.Kawabata (1998).
Interplay of signal mediators of decapentaplegic (Dpp): molecular characterization of mothers against dpp, Medea, and daughters against dpp.
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9597142 J.D.Klemm, S.L.Schreiber, and G.R.Crabtree (1998).
Dimerization as a regulatory mechanism in signal transduction.
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9759503 J.Massagué (1998).
TGF-beta signal transduction.
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9582123 J.R.Howe, S.Roth, J.C.Ringold, R.W.Summers, H.J.Järvinen, P.Sistonen, I.P.Tomlinson, R.S.Houlston, S.Bevan, F.A.Mitros, E.M.Stone, and L.A.Aaltonen (1998).
Mutations in the SMAD4/DPC4 gene in juvenile polyposis.
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9770450 K.F.Ahmad, C.K.Engel, and G.G.Privé (1998).
Crystal structure of the BTB domain from PLZF.
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PDB code: 1buo
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Mads and Smads in TGF beta signalling.
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9670020 M.Kawabata, H.Inoue, A.Hanyu, T.Imamura, and K.Miyazono (1998).
Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors.
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9720756 M.Kawabata, T.Imamura, and K.Miyazono (1998).
Signal transduction by bone morphogenetic proteins.
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9529613 M.Kretzschmar, and J.Massagué (1998).
SMADs: mediators and regulators of TGF-beta signaling.
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Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2.
  Proc Natl Acad Sci U S A, 95, 9378-9383.  
9463378 R.S.Lo, Y.G.Chen, Y.Shi, N.P.Pavletich, and J.Massagué (1998).
The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-beta receptors.
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9670811 R.W.Padgett, P.Das, and S.Krishna (1998).
TGF-beta signaling, Smads, and tumor suppressors.
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9606191 S.Dennler, S.Itoh, D.Vivien, P.ten Dijke, S.Huet, and J.M.Gauthier (1998).
Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.
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9707553 T.Shioda, R.J.Lechleider, S.L.Dunwoodie, H.Li, T.Yahata, M.P.de Caestecker, M.H.Fenner, A.B.Roberts, and K.J.Isselbacher (1998).
Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator.
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The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation.
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Smad proteins act in combination with synergistic and antagonistic regulators to target Dpp responses to the Drosophila mesoderm.
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9520423 X.Yang, C.Li, X.Xu, and C.Deng (1998).
The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice.
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  9679059 Y.G.Chen, A.Hata, R.S.Lo, D.Wotton, Y.Shi, N.Pavletich, and J.Massagué (1998).
Determinants of specificity in TGF-beta signal transduction.
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9741623 Y.Shi, Y.F.Wang, L.Jayaraman, H.Yang, J.Massagué, and N.P.Pavletich (1998).
Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling.
  Cell, 94, 585-594.
PDB code: 1mhd
  9389648 F.Liu, C.Pouponnot, and J.Massagué (1997).
Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes.
  Genes Dev, 11, 3157-3167.  
9406542 J.Janin (1997).
Specific versus non-specific contacts in protein crystals.
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  9372933 J.M.Yingling, M.B.Datto, C.Wong, J.P.Frederick, N.T.Liberati, and X.F.Wang (1997).
Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein.
  Mol Cell Biol, 17, 7019-7028.  
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