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Protein

Mothers against decapentaplegic homolog 4

Gene

SMAD4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). 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 synergistic 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.By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi71ZincBy similarity1
Metal bindingi115ZincBy similarity1
Metal bindingi127ZincBy similarity1
Metal bindingi132ZincBy similarity1
Sitei515Necessary for heterotrimerization1

GO - Molecular functioni

  • chromatin binding Source: Ensembl
  • core promoter proximal region sequence-specific DNA binding Source: UniProtKB
  • identical protein binding Source: BHF-UCL
  • I-SMAD binding Source: BHF-UCL
  • metal ion binding Source: UniProtKB-KW
  • protein homodimerization activity Source: BHF-UCL
  • RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: NTNU_SB
  • R-SMAD binding Source: BHF-UCL
  • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding Source: NTNU_SB
  • transcription factor activity, RNA polymerase II transcription factor binding Source: Ensembl
  • transcription regulatory region DNA binding Source: BHF-UCL
  • transforming growth factor beta receptor, common-partner cytoplasmic mediator activity Source: BHF-UCL

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000141646-MONOMER.
ReactomeiR-HSA-1181150. Signaling by NODAL.
R-HSA-1502540. Signaling by Activin.
R-HSA-201451. Signaling by BMP.
R-HSA-2173789. TGF-beta receptor signaling activates SMADs.
R-HSA-2173795. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
R-HSA-2173796. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
R-HSA-3311021. SMAD4 MH2 Domain Mutants in Cancer.
R-HSA-3315487. SMAD2/3 MH2 Domain Mutants in Cancer.
R-HSA-452723. Transcriptional regulation of pluripotent stem cells.
R-HSA-5689880. Ub-specific processing proteases.
SignaLinkiQ13485.
SIGNORiQ13485.

Names & Taxonomyi

Protein namesi
Recommended name:
Mothers against decapentaplegic homolog 4
Short name:
MAD homolog 4
Short name:
Mothers against DPP homolog 4
Alternative name(s):
Deletion target in pancreatic carcinoma 4
SMAD family member 4
Short name:
SMAD 4
Short name:
Smad4
Short name:
hSMAD4
Gene namesi
Name:SMAD4
Synonyms:DPC4, MADH4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 18

Organism-specific databases

HGNCiHGNC:6770. SMAD4.

Subcellular locationi

GO - Cellular componenti

  • activin responsive factor complex Source: BHF-UCL
  • cytoplasm Source: BHF-UCL
  • cytosol Source: Reactome
  • nuclear chromatin Source: BHF-UCL
  • nucleoplasm Source: Reactome
  • nucleus Source: BHF-UCL
  • SMAD protein complex Source: UniProtKB
  • transcription factor complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Pancreatic cancer (PNCA)1 Publication
The gene represented in this entry may be involved in disease pathogenesis.
Disease descriptionA malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.
See also OMIM:260350
Juvenile polyposis syndrome (JPS)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAutosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers.
See also OMIM:174900
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_022833330E → G in JPS. 1 PublicationCorresponds to variant rs281875324dbSNPEnsembl.1
Natural variantiVAR_019571352G → R in JP/HHT and JPS. 2 PublicationsCorresponds to variant rs121912581dbSNPEnsembl.1
Natural variantiVAR_019572361R → C in JPS. 1 PublicationCorresponds to variant rs80338963dbSNPEnsembl.1
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionJP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown.
See also OMIM:175050
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_019571352G → R in JP/HHT and JPS. 2 PublicationsCorresponds to variant rs121912581dbSNPEnsembl.1
Natural variantiVAR_019573386G → D in JP/HHT. 1 PublicationCorresponds to variant rs28936393dbSNPEnsembl.1
Colorectal cancer (CRC)1 Publication
The disease may be caused by mutations affecting the gene represented in this entry.
Disease descriptionA complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
See also OMIM:114500

SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.

Myhre syndrome (MYHRS)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur.
See also OMIM:139210
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067602500I → M in MYHRS. 1 PublicationCorresponds to variant rs281875320dbSNPEnsembl.1
Natural variantiVAR_067603500I → T in MYHRS; there is an enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls suggesting stabilization of the mutant protein; 8-fold increase in phosphorylated SMAD2 and SMAD3; 11-fold increase in phosphorylated SMAD1, SMAD5 and SMAD8 in cell nuclei compared to controls. 2 PublicationsCorresponds to variant rs281875321dbSNPEnsembl.1
Natural variantiVAR_067604500I → V in MYHRS. 2 PublicationsCorresponds to variant rs281875322dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi416R → S: No effect on heterotrimerization. Partially diminished transcriptional activation. 1 Publication1
Mutagenesisi496R → S: No effect on heterotrimerization. Partially diminished transcriptional activation. 1
Mutagenesisi502R → S: No effect on heterotrimerization. Greatly reduced transcriptional activation. 1 Publication1
Mutagenesisi515R → S: Reduced heterotrimerization. 1 Publication1
Mutagenesisi519K → R: Abolishes ubiquitination. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi4089.
MalaCardsiSMAD4.
MIMi114500. phenotype.
139210. phenotype.
174900. phenotype.
175050. phenotype.
260350. phenotype.
OpenTargetsiENSG00000141646.
Orphaneti1333. Familial pancreatic carcinoma.
329971. Generalized juvenile polyposis/juvenile polyposis coli.
774. Hereditary hemorrhagic telangiectasia.
2588. Myhre syndrome.
PharmGKBiPA30527.

Polymorphism and mutation databases

BioMutaiSMAD4.
DMDMi13959561.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000908611 – 552Mothers against decapentaplegic homolog 4Add BLAST552

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei37N6-acetyllysineCombined sources1
Cross-linki113Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei428N6-acetyllysineCombined sources1
Modified residuei507N6-acetyllysineCombined sources1
Cross-linki519Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication

Post-translational modificationi

Phosphorylated by PDPK1.1 Publication
Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiqitination by USP9X restores its competence to mediate TGF-beta signaling.1 Publication

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ13485.
MaxQBiQ13485.
PaxDbiQ13485.
PeptideAtlasiQ13485.
PRIDEiQ13485.

PTM databases

iPTMnetiQ13485.
PhosphoSitePlusiQ13485.

Expressioni

Gene expression databases

BgeeiENSG00000141646.
CleanExiHS_SMAD4.
ExpressionAtlasiQ13485. baseline and differential.
GenevisibleiQ13485. HS.

Organism-specific databases

HPAiCAB002312.
HPA019154.

Interactioni

Subunit structurei

Found in a complex with SMAD1 and YY1 (By similarity). Interacts with CITED2 (By similarity). Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts with ZC3H3 (By similarity). Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (PubMed:25310401).By similarity20 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself3EBI-347263,EBI-347263
AKT1P317492EBI-347263,EBI-296087
DACH1Q9UI363EBI-347263,EBI-347111
DCP1AQ9NPI64EBI-347263,EBI-374238
DLX4Q929885EBI-347263,EBI-1752755
foxh1P700562EBI-347263,EBI-9969973From a different organism.
FOXO3O435249EBI-347263,EBI-1644164
FOXO4P981772EBI-347263,EBI-4481939
GATA2P237692EBI-347263,EBI-2806671
LMO4P619685EBI-347263,EBI-2798728
NLKQ9UBE86EBI-347263,EBI-366978
RASSF5Q8WWW03EBI-347263,EBI-367390
SKIP1275512EBI-347263,EBI-347281
SKILP127573EBI-347263,EBI-2902468
SMAD1Q157979EBI-347263,EBI-1567153
SMAD2Q1579620EBI-347263,EBI-1040141
SMAD3P8402221EBI-347263,EBI-347161
SP1P080472EBI-347263,EBI-298336
TRIM33Q9UPN96EBI-347263,EBI-2214398
UBE2IP632794EBI-347263,EBI-80168
USP9XQ930082EBI-347263,EBI-302524
Usp9xP703984EBI-347263,EBI-2214043From a different organism.

GO - Molecular functioni

  • identical protein binding Source: BHF-UCL
  • I-SMAD binding Source: BHF-UCL
  • protein homodimerization activity Source: BHF-UCL
  • R-SMAD binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi110264. 217 interactors.
DIPiDIP-31512N.
IntActiQ13485. 120 interactors.
MINTiMINT-244037.
STRINGi9606.ENSP00000341551.

Structurei

Secondary structure

1552
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi288 – 291Combined sources4
Beta strandi321 – 330Combined sources10
Beta strandi333 – 342Combined sources10
Beta strandi346 – 353Combined sources8
Beta strandi359 – 363Combined sources5
Helixi364 – 366Combined sources3
Helixi374 – 380Combined sources7
Turni381 – 385Combined sources5
Beta strandi387 – 392Combined sources6
Turni393 – 395Combined sources3
Beta strandi396 – 401Combined sources6
Beta strandi403 – 405Combined sources3
Beta strandi407 – 410Combined sources4
Helixi412 – 416Combined sources5
Turni417 – 419Combined sources3
Beta strandi427 – 429Combined sources3
Beta strandi434 – 438Combined sources5
Helixi440 – 454Combined sources15
Turni455 – 458Combined sources4
Helixi461 – 464Combined sources4
Helixi493 – 497Combined sources5
Beta strandi500 – 506Combined sources7
Helixi518 – 520Combined sources3
Beta strandi521 – 529Combined sources9
Helixi530 – 541Combined sources12

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1DD1X-ray2.62A/B/C285-552[»]
1G88X-ray3.00A/B/C285-552[»]
1MR1X-ray2.85A/B319-552[»]
1U7FX-ray2.60B314-552[»]
1U7VX-ray2.70B314-549[»]
1YGSX-ray2.10A319-552[»]
5C4VX-ray2.60A/C/E314-549[»]
DisProtiDP00464.
ProteinModelPortaliQ13485.
SMRiQ13485.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ13485.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini18 – 142MH1PROSITE-ProRule annotationAdd BLAST125
Domaini323 – 552MH2PROSITE-ProRule annotationAdd BLAST230

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni275 – 320SADAdd BLAST46

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi451 – 466Poly-AlaAdd BLAST16

Domaini

The MH1 domain is required for DNA binding.
The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.

Sequence similaritiesi

Belongs to the dwarfin/SMAD family.Curated
Contains 1 MH1 (MAD homology 1) domain.PROSITE-ProRule annotation
Contains 1 MH2 (MAD homology 2) domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG3701. Eukaryota.
ENOG410XQKU. LUCA.
GeneTreeiENSGT00760000119091.
HOGENOMiHOG000286019.
HOVERGENiHBG053353.
InParanoidiQ13485.
KOiK04501.
OMAiPTEGHSI.
OrthoDBiEOG091G05Z9.
PhylomeDBiQ13485.
TreeFamiTF314923.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 1 hit.
InterProiIPR013790. Dwarfin.
IPR003619. MAD_homology1_Dwarfin-type.
IPR013019. MAD_homology_MH1.
IPR017855. SMAD_dom-like.
IPR001132. SMAD_dom_Dwarfin-type.
IPR008984. SMAD_FHA_domain.
[Graphical view]
PANTHERiPTHR13703. PTHR13703. 3 hits.
PfamiPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTiSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEiPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q13485-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK
60 70 80 90 100
KDELDSLITA ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR
110 120 130 140 150
WPDLHKNELK HVKYCQYAFD LKCDSVCVNP YHYERVVSPG IDLSGLTLQS
160 170 180 190 200
NAPSSMMVKD EYVHDFEGQP SLSTEGHSIQ TIQHPPSNRA STETYSTPAL
210 220 230 240 250
LAPSESNATS TANFPNIPVA STSQPASILG GSHSEGLLQI ASGPQPGQQQ
260 270 280 290 300
NGFTGQPATY HHNSTTTWTG SRTAPYTPNL PHHQNGHLQH HPPMPPHPGH
310 320 330 340 350
YWPVHNELAF QPPISNHPAP EYWCSIAYFE MDVQVGETFK VPSSCPIVTV
360 370 380 390 400
DGYVDPSGGD RFCLGQLSNV HRTEAIERAR LHIGKGVQLE CKGEGDVWVR
410 420 430 440 450
CLSDHAVFVQ SYYLDREAGR APGDAVHKIY PSAYIKVFDL RQCHRQMQQQ
460 470 480 490 500
AATAQAAAAA QAAAVAGNIP GPGSVGGIAP AISLSAAAGI GVDDLRRLCI
510 520 530 540 550
LRMSFVKGWG PDYPRQSIKE TPCWIEIHLH RALQLLDEVL HTMPIADPQP

LD
Length:552
Mass (Da):60,439
Last modified:November 1, 1996 - v1
Checksum:i7EE3C4647712DA90
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06687013N → S Rare variant; found in a patient with pulmonary hypertension; unknown pathological significance. 1 PublicationCorresponds to variant rs281875323dbSNPEnsembl.1
Natural variantiVAR_052022101W → G.Corresponds to variant rs2229083dbSNPEnsembl.1
Natural variantiVAR_036475130P → S in a colorectal cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_022833330E → G in JPS. 1 PublicationCorresponds to variant rs281875324dbSNPEnsembl.1
Natural variantiVAR_036476351D → N in a colorectal cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_019571352G → R in JP/HHT and JPS. 2 PublicationsCorresponds to variant rs121912581dbSNPEnsembl.1
Natural variantiVAR_019572361R → C in JPS. 1 PublicationCorresponds to variant rs80338963dbSNPEnsembl.1
Natural variantiVAR_036477361R → H in a colorectal cancer sample; somatic mutation. 1 PublicationCorresponds to variant rs377767347dbSNPEnsembl.1
Natural variantiVAR_019573386G → D in JP/HHT. 1 PublicationCorresponds to variant rs28936393dbSNPEnsembl.1
Natural variantiVAR_011380493D → H in pancreatic carcinoma. 1 PublicationCorresponds to variant rs28936392dbSNPEnsembl.1
Natural variantiVAR_067602500I → M in MYHRS. 1 PublicationCorresponds to variant rs281875320dbSNPEnsembl.1
Natural variantiVAR_067603500I → T in MYHRS; there is an enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls suggesting stabilization of the mutant protein; 8-fold increase in phosphorylated SMAD2 and SMAD3; 11-fold increase in phosphorylated SMAD1, SMAD5 and SMAD8 in cell nuclei compared to controls. 2 PublicationsCorresponds to variant rs281875321dbSNPEnsembl.1
Natural variantiVAR_067604500I → V in MYHRS. 2 PublicationsCorresponds to variant rs281875322dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF045447
, AF045438, AF045439, AF045440, AF045441, AF045442, AF045443, AF045444, AF045445, AF045446 Genomic DNA. Translation: AAC03051.1.
U44378 mRNA. Translation: AAA91041.1.
AK290770 mRNA. Translation: BAF83459.1.
CH471096 Genomic DNA. Translation: EAW62985.1.
BC002379 mRNA. Translation: AAH02379.1.
CCDSiCCDS11950.1.
PIRiS71811.
RefSeqiNP_005350.1. NM_005359.5.
UniGeneiHs.75862.

Genome annotation databases

EnsembliENST00000342988; ENSP00000341551; ENSG00000141646.
ENST00000398417; ENSP00000381452; ENSG00000141646.
GeneIDi4089.
KEGGihsa:4089.
UCSCiuc010xdp.3. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology
Mendelian genes SMAD family member 4 (SMAD4)

Leiden Open Variation Database (LOVD)

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF045447
, AF045438, AF045439, AF045440, AF045441, AF045442, AF045443, AF045444, AF045445, AF045446 Genomic DNA. Translation: AAC03051.1.
U44378 mRNA. Translation: AAA91041.1.
AK290770 mRNA. Translation: BAF83459.1.
CH471096 Genomic DNA. Translation: EAW62985.1.
BC002379 mRNA. Translation: AAH02379.1.
CCDSiCCDS11950.1.
PIRiS71811.
RefSeqiNP_005350.1. NM_005359.5.
UniGeneiHs.75862.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1DD1X-ray2.62A/B/C285-552[»]
1G88X-ray3.00A/B/C285-552[»]
1MR1X-ray2.85A/B319-552[»]
1U7FX-ray2.60B314-552[»]
1U7VX-ray2.70B314-549[»]
1YGSX-ray2.10A319-552[»]
5C4VX-ray2.60A/C/E314-549[»]
DisProtiDP00464.
ProteinModelPortaliQ13485.
SMRiQ13485.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110264. 217 interactors.
DIPiDIP-31512N.
IntActiQ13485. 120 interactors.
MINTiMINT-244037.
STRINGi9606.ENSP00000341551.

PTM databases

iPTMnetiQ13485.
PhosphoSitePlusiQ13485.

Polymorphism and mutation databases

BioMutaiSMAD4.
DMDMi13959561.

Proteomic databases

EPDiQ13485.
MaxQBiQ13485.
PaxDbiQ13485.
PeptideAtlasiQ13485.
PRIDEiQ13485.

Protocols and materials databases

DNASUi4089.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000342988; ENSP00000341551; ENSG00000141646.
ENST00000398417; ENSP00000381452; ENSG00000141646.
GeneIDi4089.
KEGGihsa:4089.
UCSCiuc010xdp.3. human.

Organism-specific databases

CTDi4089.
DisGeNETi4089.
GeneCardsiSMAD4.
GeneReviewsiSMAD4.
HGNCiHGNC:6770. SMAD4.
HPAiCAB002312.
HPA019154.
MalaCardsiSMAD4.
MIMi114500. phenotype.
139210. phenotype.
174900. phenotype.
175050. phenotype.
260350. phenotype.
600993. gene.
neXtProtiNX_Q13485.
OpenTargetsiENSG00000141646.
Orphaneti1333. Familial pancreatic carcinoma.
329971. Generalized juvenile polyposis/juvenile polyposis coli.
774. Hereditary hemorrhagic telangiectasia.
2588. Myhre syndrome.
PharmGKBiPA30527.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3701. Eukaryota.
ENOG410XQKU. LUCA.
GeneTreeiENSGT00760000119091.
HOGENOMiHOG000286019.
HOVERGENiHBG053353.
InParanoidiQ13485.
KOiK04501.
OMAiPTEGHSI.
OrthoDBiEOG091G05Z9.
PhylomeDBiQ13485.
TreeFamiTF314923.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000141646-MONOMER.
ReactomeiR-HSA-1181150. Signaling by NODAL.
R-HSA-1502540. Signaling by Activin.
R-HSA-201451. Signaling by BMP.
R-HSA-2173789. TGF-beta receptor signaling activates SMADs.
R-HSA-2173795. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
R-HSA-2173796. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
R-HSA-3311021. SMAD4 MH2 Domain Mutants in Cancer.
R-HSA-3315487. SMAD2/3 MH2 Domain Mutants in Cancer.
R-HSA-452723. Transcriptional regulation of pluripotent stem cells.
R-HSA-5689880. Ub-specific processing proteases.
SignaLinkiQ13485.
SIGNORiQ13485.

Miscellaneous databases

ChiTaRSiSMAD4. human.
EvolutionaryTraceiQ13485.
GeneWikiiMothers_against_decapentaplegic_homolog_4.
GenomeRNAii4089.
PROiQ13485.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000141646.
CleanExiHS_SMAD4.
ExpressionAtlasiQ13485. baseline and differential.
GenevisibleiQ13485. HS.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 1 hit.
InterProiIPR013790. Dwarfin.
IPR003619. MAD_homology1_Dwarfin-type.
IPR013019. MAD_homology_MH1.
IPR017855. SMAD_dom-like.
IPR001132. SMAD_dom_Dwarfin-type.
IPR008984. SMAD_FHA_domain.
[Graphical view]
PANTHERiPTHR13703. PTHR13703. 3 hits.
PfamiPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTiSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEiPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSMAD4_HUMAN
AccessioniPrimary (citable) accession number: Q13485
Secondary accession number(s): A8K405
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: November 1, 1996
Last modified: November 30, 2016
This is version 193 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 18
    Human chromosome 18: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.