UniProt Accession

 SMAD4_HUMAN; Q13485; A8K405 

Genbank Protein ID

 AF045447; AF045438; AF045439; AF045440; AF045441; AF045442; AF045443; AF045444; AF045445; AF045446; U44378; AK290770; CH471096; BC002379 

Genbank Nucleotide ID

 AAC03051.1; AAC03051.1; AAC03051.1; AAC03051.1; AAC03051.1; AAC03051.1; AAC03051.1; AAC03051.1; AAC03051.1; AAC03051.1; AAA91041.1; BAF83459.1; EAW62985.1; AAH02379.1 

Protein Name

 Mothers against decapentaplegic homolog 4 

Protein Synonyms/Alias

 MAD homolog 4; Mothers against DPP homolog 4; Deletion target in pancreatic carcinoma 4; SMAD family member 4; SMAD 4; Smad4; hSMAD4 

Gene Name

 SMAD4 

Gene Synonyms/Alias

 DPC4; MADH4 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
37	GESETFAKRAIESLV	acetylation	[1]
45	RAIESLVKKLKEKKD	acetylation	[1]
70	TNGAHPSKCVTIQRT	ubiquitination	[2]
106	WRWPDLHKNELKHVK	acetylation	[1]
113	KNELKHVKYCQYAFD	sumoylation	[3, 4, 5]
113	KNELKHVKYCQYAFD	ubiquitination	[2, 6, 7, 8, 9]
159	APSSMMVKDEYVHDF	sumoylation	[3, 4, 5, 10, 11]
385	RARLHIGKGVQLECK	ubiquitination	[2, 8]
428	APGDAVHKIYPSAYI	acetylation	[1]
507	ILRMSFVKGWGPDYP	acetylation	[1]
519	DYPRQSIKETPCWIE	ubiquitination	[2, 6, 9]

Reference

 [1] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [3] Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4.
 Lin X, Liang M, Liang YY, Brunicardi FC, Melchior F, Feng XH.
 J Biol Chem. 2003 May 23;278(21):18714-9. [PMID: 12621041]
 [4] Sumoylation of Smad4, the common Smad mediator of transforming growth factor-beta family signaling.
 Lee PS, Chang C, Liu D, Derynck R.
 J Biol Chem. 2003 Jul 25;278(30):27853-63. [PMID: 12740389]
 [5] Regulation of Smad4 sumoylation and transforming growth factor-beta signaling by protein inhibitor of activated STAT1.
 Liang M, Melchior F, Feng XH, Lin X.
 J Biol Chem. 2004 May 28;279(22):22857-65. [PMID: 15028714]
 [6] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [7] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [8] Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass.
 Povlsen LK, Beli P, Wagner SA, Poulsen SL, Sylvestersen KB, Poulsen JW, Nielsen ML, Bekker-Jensen S, Mailand N, Choudhary C.
 Nat Cell Biol. 2012 Oct;14(10):1089-98. [PMID: 23000965]
 [9] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [10] Transforming growth factor-beta-mediated signaling via the p38 MAP kinase pathway activates Smad-dependent transcription through SUMO-1 modification of Smad4.
 Ohshima T, Shimotohno K.
 J Biol Chem. 2003 Dec 19;278(51):50833-42. [PMID: 14514699]
 [11] Daxx mediates the small ubiquitin-like modifier-dependent transcriptional repression of Smad4.
 Chang CC, Lin DY, Fang HI, Chen RH, Shih HM.
 J Biol Chem. 2005 Mar 18;280(11):10164-73. [PMID: 15637079] 

Functional Description

 Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14- 3-3 protein YWHAQ which acts as a negative regulator. 

Sequence Annotation

 DOMAIN 18 142 MH1.
 DOMAIN 323 552 MH2.
 REGION 275 320 SAD.
 METAL 71 71 Zinc (By similarity).
 METAL 115 115 Zinc (By similarity).
 METAL 127 127 Zinc (By similarity).
 METAL 132 132 Zinc (By similarity).
 MOD_RES 37 37 N6-acetyllysine.
 MOD_RES 428 428 N6-acetyllysine.
 MOD_RES 507 507 N6-acetyllysine.
 CROSSLNK 519 519 Glycyl lysine isopeptide (Lys-Gly)  

Keyword

 3D-structure; Acetylation; Complete proteome; Cytoplasm; Disease mutation; DNA-binding; Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Transcription; Transcription regulation; Ubl conjugation; Zinc. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 552 AA 

Protein Sequence

Gene Ontology

 GO:0032444; C:activin responsive factor complex; IDA:BHF-UCL.
 GO:0005813; C:centrosome; IDA:HPA.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0071141; C:SMAD protein complex; IDA:UniProtKB.
 GO:0003682; F:chromatin binding; IEA:Compara.
 GO:0000987; F:core promoter proximal region sequence-specific DNA binding; IDA:UniProtKB.
 GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO:0003700; F:sequence-specific DNA binding transcription factor activity; IEA:Compara.
 GO:0030616; F:transforming growth factor beta receptor, common-partner cytoplasmic mediator activity; IDA:BHF-UCL.
 GO:0030509; P:BMP signaling pathway; IDA:BHF-UCL.
 GO:0001658; P:branching involved in ureteric bud morphogenesis; IEA:Compara.
 GO:0008283; P:cell proliferation; IEA:Compara.
 GO:0048589; P:developmental growth; IEA:Compara.
 GO:0007492; P:endoderm development; IEA:Compara.
 GO:0048859; P:formation of anatomical boundary; IEA:Compara.
 GO:0001702; P:gastrulation with mouth forming second; IEA:Compara.
 GO:0001701; P:in utero embryonic development; IEA:Compara.
 GO:0007498; P:mesoderm development; IEA:Compara.
 GO:0072133; P:metanephric mesenchyme morphogenesis; IEA:Compara.
 GO:0060548; P:negative regulation of cell death; IEA:Compara.
 GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL.
 GO:0008285; P:negative regulation of cell proliferation; IEA:Compara.
 GO:0042177; P:negative regulation of protein catabolic process; IMP:BHF-UCL.
 GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
 GO:0072134; P:nephrogenic mesenchyme morphogenesis; IEA:Compara.
 GO:0014033; P:neural crest cell differentiation; IEA:Compara.
 GO:0048663; P:neuron fate commitment; IEA:Compara.
 GO:0060021; P:palate development; ISS:BHF-UCL.
 GO:0030513; P:positive regulation of BMP signaling pathway; IMP:BHF-UCL.
 GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:BHF-UCL.
 GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; ISS:BHF-UCL.
 GO:0060391; P:positive regulation of SMAD protein import into nucleus; ISS:BHF-UCL.
 GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
 GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
 GO:0051098; P:regulation of binding; IEA:Compara.
 GO:0051797; P:regulation of hair follicle development; IEA:Compara.
 GO:0032909; P:regulation of transforming growth factor beta2 production; IMP:BHF-UCL.
 GO:0001666; P:response to hypoxia; IMP:BHF-UCL.
 GO:0048733; P:sebaceous gland development; IEA:Compara.
 GO:0007183; P:SMAD protein complex assembly; IDA:BHF-UCL.
 GO:0060395; P:SMAD protein signal transduction; IDA:BHF-UCL.
 GO:0032525; P:somite rostral/caudal axis specification; IEA:Compara.
 GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
 GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL. 

Interpro

 IPR013790; Dwarfin.
 IPR003619; MAD_homology1_Dwarfin-type.
 IPR013019; MAD_homology_MH1.
 IPR017855; SMAD_dom-like.
 IPR001132; SMAD_dom_Dwarfin-type.
 IPR008984; SMAD_FHA_domain. 

Pfam

 PF03165; MH1
 PF03166; MH2 

SMART

 SM00523; DWA
 SM00524; DWB 

PROSITE

 PS51075; MH1
 PS51076; MH2 

PRINTS