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This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasng blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, Aug 2017]
SMAD4 (SMAD Family Member 4) is a Protein Coding gene. Diseases associated with SMAD4 include Myhre Syndrome and Juvenile Polyposis Syndrome. Among its related pathways are Transcriptional activity of SMAD2/SMAD3-SMAD4 heterotrimer and Signal transduction_PKA signaling. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and sequence-specific DNA binding. An important paralog of this gene is SMAD1.
GeneHancer (GH) Identifier | GH Type | GH Score |
GH Sources | Gene Association Score | Total Score | TSS distance (kb) | Number of Genes Away | Size (kb) | Transcription Factor Binding Sites |
Gene Targets |
---|---|---|---|---|---|---|---|---|---|---|
GH18J051027 | Promoter/Enhancer | 1.6 | Ensembl ENCODE CraniofacialAtlas | 600.7 | +2.0 | 1952 | 5.3 | HNRNPL PRDM10 ZNF692 POLR2A BACH1 FOXA1 LARP7 PRDM1 PHF21A ZIC2 | LOC105372117 NONHSAG023864.2 SMAD4 lnc-MEX3C-4 ME2 RPL17P46 MRO lnc-SMAD4-2 ENSG00000267699 MEX3C | |
GH18J051049 | Promoter/Enhancer | 1.1 | EPDnew Ensembl ENCODE | 600.4 | +23.3 | 23317 | 5.4 | CTCF PRDM1 ZNF143 RXRB REST RAD21 TRIM22 RELB SMC3 ELF1 | SMAD4 RPL17P46 MRO ME2 HSALNG0121563 LOC105372117 ENSG00000267699 MEX3C | |
GH18J051028 | Promoter | 0.3 | Ensembl | 600.7 | -0.9 | -893 | 0.2 | SMAD4 lnc-SMAD4-2 ME2 LOC105372117 ENSG00000267699 | ||
GH18J051048 | Promoter | 0.3 | EPDnew | 600.4 | +20.3 | 20284 | 0.1 | SMAD4 MRO RPL17P46 HSALNG0121563 LOC105372117 ENSG00000267699 MEX3C | ||
GH18J051058 | Promoter | 0.3 | EPDnew | 600.3 | +29.7 | 29735 | 0.1 | SMAD4 HSALNG0121563 LOC105372117 ENSG00000267699 MEX3C |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000976 | transcription regulatory region sequence-specific DNA binding | IDA | 17438144 |
GO:0000977 | RNA polymerase II regulatory region sequence-specific DNA binding | IEA | -- |
GO:0000978 | RNA polymerase II proximal promoter sequence-specific DNA binding | IDA | 9389648 |
GO:0000981 | DNA-binding transcription factor activity, RNA polymerase II-specific | ISM | 19274049 |
GO:0000987 | proximal promoter sequence-specific DNA binding | IDA | 18832382 |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000790 | nuclear chromatin | IDA,ISA | -- |
GO:0005623 | cell | IEA | -- |
GO:0005634 | nucleus | IEA,IDA | 9311995 |
GO:0005654 | nucleoplasm | IDA,TAS | -- |
GO:0005667 | transcription factor complex | IEA,IPI | 12374795 |
SuperPathway | Contained pathways | ||
---|---|---|---|
1 | SMAD2/3 MH2 Domain Mutants in Cancer | ||
2 | Transcriptional activity of SMAD2/SMAD3-SMAD4 heterotrimer | ||
3 | Endometrial cancer | ||
4 | TGF-Beta Pathway |
TGF-Beta Pathway
.60
JAK-STAT Pathway
.57
|
JNK Pathway
.51
|
5 | Signaling by BMP |
.33
|
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000122 | negative regulation of transcription by RNA polymerase II | TAS | -- |
GO:0001541 | ovarian follicle development | IEA | -- |
GO:0001658 | branching involved in ureteric bud morphogenesis | IEA | -- |
GO:0001666 | response to hypoxia | IMP | 12411310 |
GO:0001701 | in utero embryonic development | IEA | -- |
Name | Status | Disease Links | Group | Role | Mechanism of Action | Clinical Trials |
---|---|---|---|---|---|---|
Capecitabine | Approved, Investigational | Pharma | RNA processing inhibitor and thymidylate synthase inhibitor, F-pyrimidines | 1669 | ||
Gemcitabine | Approved | Pharma | Ribonucleotide reductase and DNA synthesis inhibitor, Nucleoside Analogs | 2451 | ||
Paclitaxel | Approved, Vet_approved | Pharma | Tubulin and Bcl2 inhibitor, Taxanes | 3701 | ||
Pirfenidone | Approved, Investigational | Pharma | TGF-β production inhibitor, Antifibrotic agent; regulates cytokine levels in vivo | 86 | ||
Albumin-Bound Paclitaxel | Pharma | 3701 |
Name | Synonyms | Role | CAS Number | PubChem IDs | PubMed IDs |
---|
Compound | Action | Cas Number |
---|---|---|
LDN193189 Hydrochloride | ALK inhibitor,potent and selective | 1062368-62-0 |
LY364947 | 396129-53-6 | |
Pirfenidone | TGF-β production inhibitor | 53179-13-8 |
RepSox | ALK5 inhibitor,potent and selective | 446859-33-2 |
ExUns: | 1 | ^ | 2 | ^ | 3a | · | 3b | ^ | 4 | ^ | 5 | ^ | 6a | · | 6b | · | 6c | ^ | 7a | · | 7b | · | 7c | ^ | 8a | · | 8b | ^ | 9a | · | 9b | ^ | 10 | ^ | 11 | ^ | 12 | ^ | 13 | ^ | 14a | · | 14b | ^ | 15 | ^ | 16 | ^ | 17 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SP1: | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP2: | - | - | |||||||||||||||||||||||||||||||||||||||||||||||
SP3: | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||
SP4: | |||||||||||||||||||||||||||||||||||||||||||||||||
SP5: | |||||||||||||||||||||||||||||||||||||||||||||||||
SP6: | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP7: | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||||
SP8: | - | ||||||||||||||||||||||||||||||||||||||||||||||||
SP9: | |||||||||||||||||||||||||||||||||||||||||||||||||
SP10: | - | - |
This gene was present in the common ancestor of animals.
Organism | Taxonomy | Gene | Similarity | Type | Details |
---|---|---|---|---|---|
Chimpanzee (Pan troglodytes) |
Mammalia | SMAD4 30 31 |
|
OneToOne | |
Dog (Canis familiaris) |
Mammalia | MADH4 31 |
|
OneToOne | |
SMAD4 30 |
|
||||
Platypus (Ornithorhynchus anatinus) |
Mammalia | -- 31 |
|
OneToMany | |
-- 31 |
|
OneToMany | |||
Cow (Bos Taurus) |
Mammalia | SMAD4 30 31 |
|
OneToOne | |
Oppossum (Monodelphis domestica) |
Mammalia | -- 31 |
|
OneToMany | |
-- 31 |
|
OneToMany | |||
Mouse (Mus musculus) |
Mammalia | Smad4 30 17 31 |
|
OneToOne | |
Rat (Rattus norvegicus) |
Mammalia | Smad4 30 |
|
||
Chicken (Gallus gallus) |
Aves | SMAD7A 31 |
|
ManyToMany | |
Lizard (Anolis carolinensis) |
Reptilia | SMAD4 31 |
|
OneToOne | |
Tropical Clawed Frog (Silurana tropicalis) |
Amphibia | smad4.1 30 |
|
||
Str.8149 30 |
|
||||
African clawed frog (Xenopus laevis) |
Amphibia | Xl.885 30 |
|
||
Zebrafish (Danio rerio) |
Actinopterygii | smad4 31 |
|
OneToMany | |
SMAD4 (6 of 6) 31 |
|
OneToMany | |||
SMAD4 (5 of 6) 31 |
|
OneToMany | |||
zmp:0000000768 30 |
|
||||
CT955987.1 31 |
|
OneToMany | |||
SMAD4 (3 of 6) 31 |
|
OneToMany | |||
SMAD4 (4 of 6) 31 |
|
OneToMany | |||
madh4 30 |
|
||||
Rainbow Trout (Oncorhynchus mykiss) |
Actinopterygii | Omy.2009 30 |
|
||
Fruit Fly (Drosophila melanogaster) |
Insecta | Med 30 31 |
|
OneToOne | |
Worm (Caenorhabditis elegans) |
Secernentea | sma-4 31 |
|
OneToOne | |
Sea Squirt (Ciona savignyi) |
Ascidiacea | CSA.8788 31 |
|
OneToOne |
SNP ID | Clinical significance and condition | Chr 18 pos | Variation | AA Info | Type |
---|---|---|---|---|---|
24797 | Benign: Juvenile polyposis syndrome | 51,059,834(+) | T/. | INTRON_VARIANT | |
639978 | Uncertain Significance: Juvenile polyposis syndrome | 51,076,681(+) | C/T | MISSENSE_VARIANT | |
640141 | Uncertain Significance: Juvenile polyposis syndrome | 51,047,049(+) | G/C | INITIATIOR_CODON_VARIANT,MISSENSE_VARIANT | |
640252 | Uncertain Significance: Juvenile polyposis syndrome; Hereditary cancer-predisposing syndrome | 51,076,650(+) | C/T | MISSENSE_VARIANT | |
641352 | Uncertain Significance: Juvenile polyposis syndrome | 51,058,143(+) | T/G | MISSENSE_VARIANT |
Variant ID | Type | Subtype | PubMed ID |
---|---|---|---|
esv3342561 | CNV | insertion | 20981092 |
esv3583062 | CNV | loss | 25503493 |
Disorder | Aliases | PubMed IDs |
---|---|---|
myhre syndrome |
|
|
juvenile polyposis syndrome |
|
|
juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome |
|
|
pancreatic cancer |
|
|
generalized juvenile polyposis/juvenile polyposis coli |
|
|