SMAD4 SMAD family member 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: SMAD4provided by HGNC
Official Full Name: SMAD family member 4provided by HGNC
Primary source: HGNC:HGNC:6770
See related: Ensembl:ENSG00000141646 MIM:600993; AllianceGenome:HGNC:6770
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: JIP; DPC4; MADH4; MYHRS
Summary: 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 increasing 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, May 2022]
Expression: Ubiquitous expression in thyroid (RPKM 12.0), endometrium (RPKM 10.8) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 18q21.2

Exon count:: 14

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	18	NC_000018.10 (51030213..51085042)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	18	NC_060942.1 (51231926..51286759)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	18	NC_000018.9 (48556583..48611412)

Chromosome 18 - NC_000018.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

TIF1gamma and SMAD4 regulation in colorectal cancer: impact on cell proliferation and liver metastasis.
Title: TIF1γ and SMAD4 regulation in colorectal cancer: impact on cell proliferation and liver metastasis.
FLRT3 and TGF-beta/SMAD4 signalling: Impacts on apoptosis, autophagy and ion channels in supraventricular tachycardia.
Title: FLRT3 and TGF-β/SMAD4 signalling: Impacts on apoptosis, autophagy and ion channels in supraventricular tachycardia.
LINC00909 up-regulates pluripotency factors and promotes cancer stemness and metastasis in pancreatic ductal adenocarcinoma by targeting SMAD4.
Title: LINC00909 up-regulates pluripotency factors and promotes cancer stemness and metastasis in pancreatic ductal adenocarcinoma by targeting SMAD4.
Epidermal Growth Factor-Like Repeats and Discoidin I-Like Domains 3 Deficiency Attenuates Dilated Cardiomyopathy by Inhibiting Ubiquitin Specific Peptidase 10 Dependent Smad4 Deubiquitination.
Title: Epidermal Growth Factor-Like Repeats and Discoidin I-Like Domains 3 Deficiency Attenuates Dilated Cardiomyopathy by Inhibiting Ubiquitin Specific Peptidase 10 Dependent Smad4 Deubiquitination.
Oncostatin M/Oncostatin M Receptor Signal Induces Radiation-Induced Heart Fibrosis by Regulating SMAD4 in Fibroblast.
Title: Oncostatin M/Oncostatin M Receptor Signal Induces Radiation-Induced Heart Fibrosis by Regulating SMAD4 in Fibroblast.
Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.
Title: Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.
Loss of SETD2 aggravates colorectal cancer progression caused by SMAD4 deletion through the RAS/ERK signalling pathway.
Title: Loss of SETD2 aggravates colorectal cancer progression caused by SMAD4 deletion through the RAS/ERK signalling pathway.
SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma.
Title: SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma.
Impact of Smad4 and p53 mutations on the prognosis of patients with pancreatic ductal adenocarcinoma undergoing chemotherapy.
Title: Impact of Smad4 and p53 mutations on the prognosis of patients with pancreatic ductal adenocarcinoma undergoing chemotherapy.
PRMT5 methylating SMAD4 activates TGF-beta signaling and promotes colorectal cancer metastasis.
Title: PRMT5 methylating SMAD4 activates TGF-β signaling and promotes colorectal cancer metastasis.

Submit: New GeneRIF Correction See all GeneRIFs (577)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Carcinoma of pancreas MedGen: C0235974 OMIM: 260350 GeneReviews: Not available	Compare labs
Juvenile polyposis syndrome MedGen: C0345893 OMIM: 174900 GeneReviews: Juvenile Polyposis Syndrome	Compare labs
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome MedGen: C1832942 OMIM: 175050 GeneReviews: Hereditary Hemorrhagic Telangiectasia, Juvenile Polyposis Syndrome	Compare labs
Myhre syndrome MedGen: C0796081 OMIM: 139210 GeneReviews: Myhre Syndrome	Compare labs

Copy number response

Description
Copy number response Triplosensitivity No evidence available (Last evaluated 2020-12-16) ClinGen Genome Curation Page Haploinsufficency Sufficient evidence for dosage pathogenicity (Last evaluated 2020-12-16) ClinGen Genome Curation PagePubMed

EBI GWAS Catalog

Description
A genome-wide association study of host genetic determinants of the antibody response to Anthrax Vaccine Adsorbed. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Tat	tat	HIV-1 Tat-treated pulmonary arterial smooth muscle cells downregulate levels of phosphorylated SMAD2/3 proteins and SMAD2/3-SMAD4 protein complex, which are repressed by cocaine exposure	PubMed
	tat	HIV-1 Tat-treated pulmonary arterial smooth muscle cells modulate levels of phosphorylated SMAD1/5/8 proteins and SMAD1/5/8-SMAD4 protein complex, which are repressed by cocaine exposure	PubMed
	tat	HIV-1 Tat proteins from different clades modulate differently Pur-alpha and SMAD4 to bind the JCV non-coding control region and affect differently on SMAD4 localization to the nucleus	PubMed
	tat	HIV-1 Tat enhances binding of SMAD2, -3 and -4 and their binding partner Fast1 to the JCV DNA control region (CR) to stimulate JCV gene transcription in living cells	PubMed
	tat	Smad-4 inhibits Smad-3 and HIV-1 Tat-induced transcription from the HIV-1 LTR promoter and the MCP promoter through a direct association with amino acids 1-40 of Tat	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

WI-11075 (e-PCR)
- UniSTS:79113

D8S2279 (e-PCR)
- UniSTS:473907

RH66749 (e-PCR)
- UniSTS:67183

AF010230 (e-PCR)
- UniSTS:105082

PMC86557P1 (e-PCR)
- UniSTS:273533

RH46461 (e-PCR)
- UniSTS:15242

RH75869 (e-PCR)
- UniSTS:88461

SHGC-56739 (e-PCR)
- UniSTS:9636

D18S1110 (e-PCR)
- UniSTS:70066

RH44980 (e-PCR)
- UniSTS:49355

MADH4_174 (e-PCR)
- UniSTS:277461

D18S903E (e-PCR)
- UniSTS:150513

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
contributes_to DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables DNA-binding transcription activator activity, RNA polymerase II-specific	IDA Inferred from Direct Assay more info	PubMed
contributes_to DNA-binding transcription factor activity	IDA Inferred from Direct Assay more info	PubMed
enables DNA-binding transcription factor activity	IDA Inferred from Direct Assay more info	PubMed
enables DNA-binding transcription factor activity, RNA polymerase II-specific	IBA Inferred from Biological aspect of Ancestor more info
enables DNA-binding transcription factor activity, RNA polymerase II-specific	ISA Inferred from Sequence Alignment more info
enables I-SMAD binding	IBA Inferred from Biological aspect of Ancestor more info
enables I-SMAD binding	IPI Inferred from Physical Interaction more info	PubMed
enables R-SMAD binding	IPI Inferred from Physical Interaction more info	PubMed
enables RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA Inferred from Biological aspect of Ancestor more info
enables RNA polymerase II cis-regulatory region sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables RNA polymerase II-specific DNA-binding transcription factor binding	IEA Inferred from Electronic Annotation more info
enables chromatin binding	IEA Inferred from Electronic Annotation more info
enables collagen binding	IEA Inferred from Electronic Annotation more info
enables filamin binding	IEA Inferred from Electronic Annotation more info
enables identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables metal ion binding	IEA Inferred from Electronic Annotation more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	IPI Inferred from Physical Interaction more info	PubMed
enables sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables sulfate binding	IMP Inferred from Mutant Phenotype more info	PubMed
enables transcription cis-regulatory region binding	IDA Inferred from Direct Assay more info	PubMed
enables transcription coactivator binding	IPI Inferred from Physical Interaction more info	PubMed
enables transcription corepressor binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
involved_in BMP signaling pathway	IBA Inferred from Biological aspect of Ancestor more info
involved_in BMP signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in BMP signaling pathway	IGI Inferred from Genetic Interaction more info	PubMed
involved_in BMP signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in BMP signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in DNA-templated transcription	NAS Non-traceable Author Statement more info	PubMed
involved_in ERK1 and ERK2 cascade	IEA Inferred from Electronic Annotation more info
involved_in SMAD protein signal transduction	IBA Inferred from Biological aspect of Ancestor more info
involved_in SMAD protein signal transduction	IDA Inferred from Direct Assay more info	PubMed
involved_in SMAD protein signal transduction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in SMAD protein signal transduction	ISS Inferred from Sequence or Structural Similarity more info
involved_in activin receptor signaling pathway	NAS Non-traceable Author Statement more info	PubMed
involved_in adrenal gland development	IEA Inferred from Electronic Annotation more info
involved_in anatomical structure morphogenesis	IBA Inferred from Biological aspect of Ancestor more info
involved_in atrioventricular canal development	ISS Inferred from Sequence or Structural Similarity more info
involved_in atrioventricular valve formation	ISS Inferred from Sequence or Structural Similarity more info
involved_in axon guidance	IEA Inferred from Electronic Annotation more info
involved_in brainstem development	IEA Inferred from Electronic Annotation more info
involved_in branching involved in ureteric bud morphogenesis	IEA Inferred from Electronic Annotation more info
involved_in cardiac conduction system development	NAS Non-traceable Author Statement more info	PubMed
involved_in cardiac muscle hypertrophy in response to stress	IEA Inferred from Electronic Annotation more info
involved_in cell differentiation	IBA Inferred from Biological aspect of Ancestor more info
involved_in cell population proliferation	IEA Inferred from Electronic Annotation more info
involved_in cellular response to BMP stimulus	NAS Non-traceable Author Statement more info	PubMed
involved_in cellular response to glucose stimulus	IEA Inferred from Electronic Annotation more info
involved_in cellular response to transforming growth factor beta stimulus	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in developmental growth	IEA Inferred from Electronic Annotation more info
involved_in embryonic digit morphogenesis	IEA Inferred from Electronic Annotation more info
involved_in endocardial cell differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in endothelial cell activation	IEA Inferred from Electronic Annotation more info
involved_in epithelial cell migration	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in epithelial to mesenchymal transition	IGI Inferred from Genetic Interaction more info	PubMed
involved_in epithelial to mesenchymal transition	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in epithelial to mesenchymal transition involved in endocardial cushion formation	IEA Inferred from Electronic Annotation more info
involved_in extrinsic apoptotic signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in female gonad morphogenesis	IEA Inferred from Electronic Annotation more info
involved_in formation of anatomical boundary	IEA Inferred from Electronic Annotation more info
involved_in gastrulation with mouth forming second	IEA Inferred from Electronic Annotation more info
involved_in in utero embryonic development	IEA Inferred from Electronic Annotation more info
involved_in interleukin-6-mediated signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in intracellular iron ion homeostasis	ISS Inferred from Sequence or Structural Similarity more info
involved_in intracellular signal transduction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in left ventricular cardiac muscle tissue morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in mesendoderm development	IEA Inferred from Electronic Annotation more info
involved_in metanephric mesenchyme morphogenesis	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of ERK1 and ERK2 cascade	ISS Inferred from Sequence or Structural Similarity more info
acts_upstream_of_or_within negative regulation of canonical Wnt signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of cardiac muscle hypertrophy	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of cardiac myofibril assembly	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of cell growth	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of cell population proliferation	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of protein catabolic process	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info
involved_in nephrogenic mesenchyme morphogenesis	IEA Inferred from Electronic Annotation more info
involved_in neural crest cell differentiation	IEA Inferred from Electronic Annotation more info
involved_in neuron fate specification	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in osteoblast differentiation	IEA Inferred from Electronic Annotation more info
involved_in outflow tract septum morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in ovarian follicle development	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of SMAD protein signal transduction	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of cardiac muscle cell apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of cell proliferation involved in heart valve morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of epithelial to mesenchymal transition	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of extracellular matrix assembly	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of follicle-stimulating hormone secretion	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of gene expression	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of luteinizing hormone secretion	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of miRNA transcription	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of transcription by RNA polymerase II	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of transcription by RNA polymerase II	TAS Traceable Author Statement more info	PubMed
involved_in positive regulation of transforming growth factor beta receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of DNA-templated transcription	NAS Non-traceable Author Statement more info	PubMed
involved_in regulation of hair follicle development	IEA Inferred from Electronic Annotation more info
involved_in regulation of transcription by RNA polymerase II	IBA Inferred from Biological aspect of Ancestor more info
involved_in regulation of transforming growth factor beta receptor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of transforming growth factor beta2 production	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in response to hypoxia	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in response to transforming growth factor beta	IDA Inferred from Direct Assay more info	PubMed
involved_in sebaceous gland development	IEA Inferred from Electronic Annotation more info
involved_in secondary palate development	ISS Inferred from Sequence or Structural Similarity more info
involved_in seminiferous tubule development	IEA Inferred from Electronic Annotation more info
involved_in single fertilization	IEA Inferred from Electronic Annotation more info
involved_in somite rostral/caudal axis specification	IEA Inferred from Electronic Annotation more info
involved_in spermatogenesis	IEA Inferred from Electronic Annotation more info
involved_in transcription by RNA polymerase II	IEA Inferred from Electronic Annotation more info
involved_in transforming growth factor beta receptor signaling pathway	IBA Inferred from Biological aspect of Ancestor more info
involved_in transforming growth factor beta receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in transforming growth factor beta receptor signaling pathway	IGI Inferred from Genetic Interaction more info	PubMed
involved_in transforming growth factor beta receptor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in transforming growth factor beta receptor signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in transforming growth factor beta receptor signaling pathway	NAS Non-traceable Author Statement more info	PubMed
involved_in uterus development	IEA Inferred from Electronic Annotation more info
involved_in ventricular septum morphogenesis	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
part_of SMAD protein complex	IDA Inferred from Direct Assay more info	PubMed
part_of SMAD protein complex	IMP Inferred from Mutant Phenotype more info	PubMed
part_of activin responsive factor complex	IDA Inferred from Direct Assay more info	PubMed
located_in centrosome	IDA Inferred from Direct Assay more info
part_of chromatin	IDA Inferred from Direct Assay more info	PubMed
part_of chromatin	ISA Inferred from Sequence Alignment more info
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	IDA Inferred from Direct Assay more info
located_in cytosol	TAS Traceable Author Statement more info
part_of heteromeric SMAD protein complex	IBA Inferred from Biological aspect of Ancestor more info
part_of heteromeric SMAD protein complex	IPI Inferred from Physical Interaction more info	PubMed
part_of heteromeric SMAD protein complex	NAS Non-traceable Author Statement more info	PubMed
located_in nucleoplasm	IDA Inferred from Direct Assay more info
located_in nucleoplasm	TAS Traceable Author Statement more info
located_in nucleus	IDA Inferred from Direct Assay more info	PubMed
part_of transcription regulator complex	IDA Inferred from Direct Assay more info	PubMed
part_of transcription regulator complex	IPI Inferred from Physical Interaction more info	PubMed

General protein information

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Preferred Names: mothers against decapentaplegic homolog 4

Names: MAD homolog 4; SMAD, mothers against DPP homolog 4; deleted in pancreatic carcinoma locus 4; deletion target in pancreatic carcinoma 4; mothers against decapentaplegic, Drosophila, homolog of, 4

NCBI Reference Sequences (RefSeq)

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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_013013.2 RefSeqGene

Range

67174..122003

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_318

mRNA and Protein(s)

NM_001407041.1 → NP_001393970.1 mothers against decapentaplegic homolog 4 isoform a

Status: REVIEWED

Source sequence(s)

AC091551

UniProtKB/Swiss-Prot

A8K405, Q13485

UniProtKB/TrEMBL

A0A024R274

Related

ENSP00000464772.2, ENST00000590061.2
NM_001407042.1 → NP_001393971.1 mothers against decapentaplegic homolog 4 isoform a

Status: REVIEWED

Source sequence(s)

AC091551

UniProtKB/Swiss-Prot

A8K405, Q13485

UniProtKB/TrEMBL

A0A024R274

Related

ENSP00000466934.2, ENST00000589076.6
NM_001407043.1 → NP_001393972.1 mothers against decapentaplegic homolog 4 isoform b

Status: REVIEWED

Source sequence(s)

AC091551

Related

ENSP00000468611.1, ENST00000592186.5
NM_005359.6 → NP_005350.1 mothers against decapentaplegic homolog 4 isoform a

See identical proteins and their annotated locations for NP_005350.1

Status: REVIEWED

Source sequence(s)

AC091551, AU120224, BC002379, BM701399

Consensus CDS

CCDS11950.1

UniProtKB/Swiss-Prot

A8K405, Q13485

UniProtKB/TrEMBL

A0A024R274, K7ELK2

Related

ENSP00000341551.3, ENST00000342988.8

Conserved Domains (2) summary

cd10492
Location:14 → 138

MH1_SMAD_4; N-terminal Mad Homology 1 (MH1) domain in SMAD4

cd10498
Location:320 → 541

MH2_SMAD_4; C-terminal Mad Homology 2 (MH2) domain in SMAD4