Human Gene SMAD6 (ENST00000288840.10) from GENCODE V41
  Description: Homo sapiens SMAD family member 6 (SMAD6), transcript variant 3, non-coding RNA. (from RefSeq NR_027654)
RefSeq Summary (NM_005585): The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014].
Gencode Transcript: ENST00000288840.10
Gencode Gene: ENSG00000137834.15
Transcript (Including UTRs)
   Position: hg38 chr15:66,702,236-66,782,849 Size: 80,614 Total Exon Count: 4 Strand: +
Coding Region
   Position: hg38 chr15:66,703,259-66,781,535 Size: 78,277 Coding Exon Count: 4 

Page IndexSequence and LinksUniProtKB CommentsMalaCardsCTDRNA-Seq Expression
Microarray ExpressionRNA StructureProtein StructureOther SpeciesGO AnnotationsmRNA Descriptions
PathwaysOther NamesMethods
Data last updated at UCSC: 2022-05-14 09:57:26

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr15:66,702,236-66,782,849)mRNA (may differ from genome)Protein (496 aa)
Gene SorterGenome BrowserOther Species FASTAGene interactionsTable SchemaAlphaFold
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GeneCardsHGNCHPRDLynxMGIneXtProt
OMIMPubMedReactomeUniProtKBWikipedia

-  Comments and Description Text from UniProtKB
  ID: SMAD6_HUMAN
DESCRIPTION: RecName: Full=Mothers against decapentaplegic homolog 6; Short=MAD homolog 6; Short=Mothers against DPP homolog 6; AltName: Full=SMAD family member 6; Short=SMAD 6; Short=Smad6; Short=hSMAD6;
FUNCTION: Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit selectively BMP (bone morphogenetic proteins) signaling by competing with the co-SMAD SMAD4 for receptor-activated SMAD1. SMAD6 is an inhibitory SMAD (I-SMAD) or antagonistic SMAD. Binds to regulatory elements in target promoter regions.
SUBUNIT: Interacts with NEDD4L (By similarity). Interacts with WWP1 (By similarity). Interacts with RNF111 and AXIN1. Interacts with TGF-beta type I receptor superfamily members, SMAD1, HOXC8 and HOXC9. Interacts with STAMBP and PRKX.
INTERACTION: P51817:PRKX; NbExp=5; IntAct=EBI-976374, EBI-4302903; Q13950:RUNX2; NbExp=3; IntAct=EBI-976374, EBI-976402; O95630:STAMBP; NbExp=2; IntAct=EBI-4324970, EBI-396676;
SUBCELLULAR LOCATION: Nucleus.
TISSUE SPECIFICITY: Ubiquitous in various organs, with higher levels in lung. Isoform B is up-regulated in diseased heart tissue.
PTM: Phosphorylated by BMP type 1 receptor kinase and by PRKX.
PTM: Ubiquitinated by WWP1 (By similarity).
DISEASE: Defects in SMAD6 are the cause of aortic valve disease 2 (AOVD2) [MIM:614823]. A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. Note=SMAD6 variants may contribute to increased risk of congenital cardiovascular malformations (CVM). CVM is a major cause of mortality and morbidity in childhood. In most sporadic cases that cannot be attributed to particular malformation syndromes or teratogenic exposures, there remains a substantial excess familial risk, indicating a significant genetic contribution to disease susceptibility (PubMed:22275001).
SIMILARITY: Belongs to the dwarfin/SMAD family.
SIMILARITY: Contains 1 MH1 (MAD homology 1) domain.
SIMILARITY: Contains 1 MH2 (MAD homology 2) domain.

-  MalaCards Disease Associations
  MalaCards Gene Search: SMAD6
Diseases sorted by gene-association score: aortic valve disease 2* (1329), craniosynostosis 7* (879), familial bicuspid aortic valve* (247), hypoplastic left heart syndrome (6), craniosynostosis (4)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 21.58 RPKM in Lung
Total median expression: 221.72 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -448.901023-0.439 Picture PostScript Text
3' UTR -377.401314-0.287 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
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 Domains:
PF03165 - MH1 domain
PF03166 - MH2 domain

ModBase Predicted Comparative 3D Structure on O43541
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-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserGenome BrowserGenome BrowserNo orthologNo ortholog
Gene Details     
Gene Sorter     
MGIRGDEnsemblEnsembl  
Protein SequenceProtein SequenceProtein SequenceProtein Sequence  
AlignmentAlignmentAlignmentAlignment  

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding
GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding
GO:0003677 DNA binding
GO:0003682 chromatin binding
GO:0003700 transcription factor activity, sequence-specific DNA binding
GO:0005515 protein binding
GO:0030617 transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity
GO:0031625 ubiquitin protein ligase binding
GO:0034713 type I transforming growth factor beta receptor binding
GO:0042802 identical protein binding
GO:0044212 transcription regulatory region DNA binding
GO:0046872 metal ion binding
GO:0070410 co-SMAD binding
GO:0070411 I-SMAD binding
GO:0070412 R-SMAD binding
GO:0070698 type I activin receptor binding

Biological Process:
GO:0001657 ureteric bud development
GO:0003148 outflow tract septum morphogenesis
GO:0003170 heart valve development
GO:0003183 mitral valve morphogenesis
GO:0003184 pulmonary valve morphogenesis
GO:0003281 ventricular septum development
GO:0006351 transcription, DNA-templated
GO:0006355 regulation of transcription, DNA-templated
GO:0006955 immune response
GO:0007179 transforming growth factor beta receptor signaling pathway
GO:0007352 zygotic specification of dorsal/ventral axis
GO:0008285 negative regulation of cell proliferation
GO:0010991 negative regulation of SMAD protein complex assembly
GO:0030279 negative regulation of ossification
GO:0030509 BMP signaling pathway
GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway
GO:0030514 negative regulation of BMP signaling pathway
GO:0031589 cell-substrate adhesion
GO:0034616 response to laminar fluid shear stress
GO:0035904 aorta development
GO:0043066 negative regulation of apoptotic process
GO:0043627 response to estrogen
GO:0045444 fat cell differentiation
GO:0060394 negative regulation of pathway-restricted SMAD protein phosphorylation
GO:0060976 coronary vasculature development
GO:1902895 positive regulation of pri-miRNA transcription from RNA polymerase II promoter

Cellular Component:
GO:0005622 intracellular
GO:0005634 nucleus
GO:0005667 transcription factor complex
GO:0005737 cytoplasm
GO:0005794 Golgi apparatus
GO:0005829 cytosol
GO:0016604 nuclear body
GO:0032991 macromolecular complex


-  Descriptions from all associated GenBank mRNAs
  AF035528 - Homo sapiens Smad6 mRNA, complete cds.
BC012986 - Homo sapiens SMAD family member 6, mRNA (cDNA clone MGC:16155 IMAGE:3632931), complete cds.
AM909653 - Homo sapiens SMAD6 gene for SMAD family member 6, splice variant 3, isolated from epithelial cells.
AF037469 - Homo sapiens Smad6 (Smad6) mRNA, complete cds.
AF043640 - Homo sapiens Smad6 (SMAD6) mRNA, complete cds.
U59914 - Human chromosome 15 Mad homolog Smad6 mRNA, complete cds.
JD351507 - Sequence 332531 from Patent EP1572962.
JD443478 - Sequence 424502 from Patent EP1572962.
JD054794 - Sequence 35818 from Patent EP1572962.
BC029288 - Homo sapiens SMAD family member 6, mRNA (cDNA clone IMAGE:4513457).
JD125009 - Sequence 106033 from Patent EP1572962.
JD125010 - Sequence 106034 from Patent EP1572962.
JD461716 - Sequence 442740 from Patent EP1572962.
BC052569 - Homo sapiens SMAD family member 6, mRNA (cDNA clone IMAGE:5922640), with apparent retained intron.
JD407385 - Sequence 388409 from Patent EP1572962.
JD083503 - Sequence 64527 from Patent EP1572962.
JD504958 - Sequence 485982 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04144 - Endocytosis
hsa04350 - TGF-beta signaling pathway

BioCyc Knowledge Library
PWY66-11 - BMP Signalling Pathway

BioCarta from NCI Cancer Genome Anatomy Project
h_alkPathway - ALK in cardiac myocytes

Reactome (by CSHL, EBI, and GO)

Protein O43541 (Reactome details) participates in the following event(s):

R-HSA-201475 I-Smad competes with R-Smad1/5/8 for type I receptor
R-HSA-202626 I-Smad competes with Co-Smad for R-Smad1/5/8
R-HSA-201821 I-Smad binds to type I receptor, preventing Smad1/5/8 from being activated
R-HSA-8941326 RUNX2 regulates bone development
R-HSA-201451 Signaling by BMP
R-HSA-8878166 Transcriptional regulation by RUNX2
R-HSA-9006936 Signaling by TGF-beta family members
R-HSA-212436 Generic Transcription Pathway
R-HSA-162582 Signal Transduction
R-HSA-73857 RNA Polymerase II Transcription
R-HSA-74160 Gene expression (Transcription)

-  Other Names for This Gene
  Alternate Gene Symbols: A9J6M5, ENST00000288840.1, ENST00000288840.2, ENST00000288840.3, ENST00000288840.4, ENST00000288840.5, ENST00000288840.6, ENST00000288840.7, ENST00000288840.8, ENST00000288840.9, MADH6, NR_027654, O43541, O43654, Q15799, Q7Z7L4, Q96E31, Q9UKZ3, SMAD6_HUMAN, uc002aqf.1, uc002aqf.2, uc002aqf.3, uc002aqf.4, uc002aqf.5
UCSC ID: ENST00000288840.10
RefSeq Accession: NM_005585
Protein: O43541 (aka SMAD6_HUMAN or SMA6_HUMAN)
CCDS: CCDS10221.1

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.