SMAD6 SMAD family member 6 [Homo sapiens] - Gene

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Summary

Official Symbol: SMAD6provided by HGNC
Official Full Name: SMAD family member 6provided by HGNC
Primary source: HGNC:6772
See related: Ensembl:ENSG00000137834; HPRD:04240; MIM:602931; Vega:OTTHUMG00000133218
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: MADH6; MADH7; HsT17432
Summary: 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 encoding different isoforms have been found for this gene.[provided by RefSeq, May 2009]

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Genomic context

Location :: 15q21-q22

Sequence :: Chromosome: 15; NC_000015.9 (66994674..67074338)

See SMAD6 in Epigenomics, MapViewer

Chromosome 15 - NC_000015.9 Genomic Context describing neighboring genes

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Genomic regions, transcripts, and products

Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

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Bibliography

GeneRIFs: Gene References Into Functions What's a GeneRIF?

Haplotype analysis further revealed that two haplotype blocks within SMAD6 were significantly associated with decreased ovarian cancer risk, as compared to the most common haplotype.
Title: Genetic variants in TGF-β pathway are associated with ovarian cancer risk.
results suggest that MyD88 degradation driven by the Smad6-Smurf pathway is a novel mechanism for TGF-beta1-mediated negative regulation of MyD88-dependent pro-inflammatory signalling
Title: Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling.
Data show that Runx1, in conjunction with Fli1, Gata2, and Scl, directly regulates the expression of Smad6 in the aorta-gonad-mesonephros region in the developing embryo, where hematopoietic stem cells originate.
Title: A Runx1-Smad6 rheostat controls Runx1 activity during embryonic hematopoiesis.
Smad6 and Smad7, inhibitors of BMP signaling, were up-regulated in HFE-mutant hereditary hemochromatosis compared to controls, disruptin bone morphogenic protein signaling.
Title: Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis.
Smad6 together with Smad2 may be prognostic factors, independent of nodal status in oral SCC after curative resection
Title: Smad2 and Smad6 as predictors of overall survival in oral squamous cell carcinoma patients.
Smad6 gene is a candidate for the genetic determinants of bone mineral density in postmenopausal women.
Title: Bone mass effects of a Smad6 gene polymorphism in Japanese postmenopausal women.
Study data demonstrates downregulated SMAD6 expression in psoriatic skin.
Title: Downregulation of SMAD2, 4 and 6 mRNA and TGFbeta receptor I mRNA in lesional and non-lesional psoriatic skin.
Stimulation of Smad 6 inhibits ERK activation and thus results in a negative feedback loop to fine-tune BMP signaling in human umbilical vein endothelial cells.
Title: ERK signaling is a central regulator for BMP-4 dependent capillary sprouting.
Splice variant Smad6B, in human prostatic and rodent testicular cell lines, exhibits a truncated C-terminus lacking the entire MH-2 domain and most parts of the linker region.
Title: Identification of a new human Smad6 splice variant.
Knockdown of SMAD6 led to the activation of TGF-beta signaling through up-regulation of plasminogen activator inhibitor-1 and phosphorylation of SMAD2/3 in NSCLC.
Title: SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-beta homeostasis in lung cancer cells.

Submit: New GeneRIF Correction See all (26)

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Phenotypes

Review eQTL and phenotype association data in this region using PheGenI

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HIV-1 protein interactions

Protein	Gene	Interaction	Pubs
Tat	tat	SMAD6 expression and its phosphorylation, in response to bone morphogenetic protein-2 (BMP2) treatment, is downregulated by HIV-1 Tat treatment in the macrophage cell line U937	PubMed

Go to the HIV-1, Human Protein Interaction Database

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Products	Interactant	Other Gene	Source	Pubs	Description
O43541	O00238	BMPR1B	HPRD	PubMed
O43541	P31273	HOXC8	HPRD	PubMed
O43541	O43318	MAP3K7	HPRD	PubMed
O43541	Q6ZNA4	RNF111	HPRD	PubMed
O43541	Q13950	RUNX2	HPRD	PubMed
O43541	Q15797	SMAD1	HPRD	PubMed
O43541	O15105	SMAD7	HPRD	PubMed
O43541	Q9HCE7	SMURF1	HPRD	PubMed
O43541	Q9HAU4	SMURF2	HPRD	PubMed
O43541	O95630	STAMBP	HPRD	PubMed
O43541	Q9Y3F4	STRAP	HPRD	PubMed
O43541	Q15750	TAB1	HPRD	PubMed
O43541	P36897	TGFBR1	HPRD	PubMed
O43541	P50616	TOB1	HPRD	PubMed
BioGRID:110266	BioGRID:107869	CTBP1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:109464	HOXC8	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex; Two-hybrid
BioGRID:110266	BioGRID:112748	MAP3K7	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:111583	MAPK6	BioGRID	PubMed	Two-hybrid
BioGRID:110266	BioGRID:110811	NEDD4	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:119624	PIAS4	BioGRID	PubMed	Affinity Capture-Western; Two-hybrid
BioGRID:110266	BioGRID:120146	RNF111	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:114676	RPS6KA5	BioGRID	PubMed	Two-hybrid
BioGRID:110266	BioGRID:110261	SMAD1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:110262	SMAD2	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:110264	SMAD4	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:110265	SMAD5	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:110267	SMAD7	BioGRID	PubMed	Affinity Capture-Western; Two-hybrid
BioGRID:110266	BioGRID:121411	SMURF1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:122265	SMURF2	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:115863	STAMBP	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:116342	STRAP	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:115717	TAB1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:114374	TSC22D1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:116243	WWP1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:115684	YAP1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110266	BioGRID:112796	ZEB1	BioGRID	PubMed	Affinity Capture-Western

Function	Evidence Code	Pubs
I-SMAD binding	IPI Inferred from Physical Interaction more info	PubMed
R-SMAD binding	IPI Inferred from Physical Interaction more info	PubMed
chromatin binding	IDA Inferred from Direct Assay more info	PubMed
co-SMAD binding	IPI Inferred from Physical Interaction more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
sequence-specific DNA binding transcription factor activity	IEA Inferred from Electronic Annotation more info
transcription regulatory region DNA binding	IDA Inferred from Direct Assay more info	PubMed
transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity	IDA Inferred from Direct Assay more info	PubMed
transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity	IMP Inferred from Mutant Phenotype more info	PubMed
type I activin receptor binding	IDA Inferred from Direct Assay more info	PubMed
type I transforming growth factor beta receptor binding	IDA Inferred from Direct Assay more info	PubMed
ubiquitin protein ligase binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
BMP signaling pathway	TAS Traceable Author Statement more info
cell-substrate adhesion	IMP Inferred from Mutant Phenotype more info	PubMed
immune response	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of BMP signaling pathway	IDA Inferred from Direct Assay more info	PubMed
negative regulation of SMAD protein complex assembly	IDA Inferred from Direct Assay more info	PubMed
negative regulation of apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of cysteine-type endopeptidase activity involved in apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of pathway-restricted SMAD protein phosphorylation	IDA Inferred from Direct Assay more info	PubMed
negative regulation of pathway-restricted SMAD protein phosphorylation	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of transforming growth factor beta receptor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of S phase of mitotic cell cycle	IMP Inferred from Mutant Phenotype more info	PubMed
response to estrogen stimulus	IEA Inferred from Electronic Annotation more info
response to laminar fluid shear stress	IEP Inferred from Expression Pattern more info	PubMed
transforming growth factor beta receptor signaling pathway	TAS Traceable Author Statement more info
ureteric bud development	IEA Inferred from Electronic Annotation more info
zygotic specification of dorsal/ventral axis	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
cytoplasm	TAS Traceable Author Statement more info	PubMed
cytosol	TAS Traceable Author Statement more info
intracellular	IEA Inferred from Electronic Annotation more info
nucleus	IDA Inferred from Direct Assay more info	PubMed
transcription factor complex	IEA Inferred from Electronic Annotation more info

General protein information

Preferred Names: mothers against decapentaplegic homolog 6

Names: mothers against decapentaplegic homolog 6; SMAD 6; hSMAD6; MAD homolog 6; mothers against DPP homolog 6; SMAD, mothers against DPP homolog 6; Mothers against decapentaplegic, drosophila, homolog of, 6

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NCBI Reference Sequences (RefSeq)

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_012244.1 RefSeqGene

Range

5001..84665

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001142861.2 → NP_001136333.1 mothers against decapentaplegic homolog 6 isoform 2

Status: REVIEWED

Description

Transcript Variant: This variant uses a different exon at the 5' terminus, compared to variant 1. The resulting isoform (2) has a shorter and distinct N-terminus with a truncated Mad homolog (MH)-1 domain, compared to isoform 1. The variant is also known as SMAD6s.

Source sequence(s)

AC013564, CN314453, U59914

Consensus CDS

CCDS45287.1

UniProtKB/Swiss-Prot

O43541

Related

ENSP00000345054, ENST00000338426

Conserved Domains (1) summary

cd10499
Location:61 – 233
Blast Score: 934

MH2_SMAD_6; C-terminal Mad Homology 2 (MH2) domain in SMAD6
NM_005585.4 → NP_005576.3 mothers against decapentaplegic homolog 6 isoform 1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longer isoform (1).

Source sequence(s)

AF035528, BC012986, BC029288, CA406301, CN314453, CN314455, U59914

Consensus CDS

CCDS10221.1

UniProtKB/Swiss-Prot

O43541

Related

ENSP00000288840, OTTHUMP00000164291, ENST00000288840, OTTHUMT00000256953

Conserved Domains (2) summary

cd10493
Location:170 – 271
Blast Score: 394

MH1_SMAD_6; N-terminal Mad Homology 1 (MH1) domain in SMAD6

cd10499
Location:322 – 494
Blast Score: 933

MH2_SMAD_6; C-terminal Mad Homology 2 (MH2) domain in SMAD6

RNA

NR_027654.1 RNA Sequence

Description

Transcript Variant: This variant (3), also known as SMAD6B, includes an alternate exon, compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon, as used in variant 1, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AF035528, AM909653, BC029288, CA406301, CN314453, CN314455, U59914

RefSeqs of Annotated Genomes: Build 37.3

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p5 Primary Assembly

Genomic

NC_000015.9 Reference GRCh37.p5 Primary Assembly

Range

66994674..67074338

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000147.1 Alternate HuRef

Range

43830247..43909482

Download

GenBank, FASTA, Sequence Viewer (Graphics)

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Related Sequences

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	AC013564.7	None
genomic	AC110048.2 (123736..146280)	None
genomic	AF041065.1	AAF14343.1
genomic	AF101474.1	AAF06841.1
genomic	CH471082.1	EAW77784.1
		EAW77785.1
		EAW77786.1
mRNA	AF035528.1	AAB94137.1
mRNA	AF037469.1	AAC82331.1
mRNA	AF043640.1	AAC00497.1
mRNA	AM909653.1	CAP20377.1
mRNA	BC012986.2	AAH12986.1
mRNA	BC029288.1	None
mRNA	BC052569.1	None
mRNA	BU154759.1	None
mRNA	CA406301.1	None
mRNA	CB055216.1	None
mRNA	CN314453.1	None
mRNA	CN314455.1	None
mRNA	U59914.1	AAC50792.1