SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))

2004-08-01   Raphael Saffroy , Antoinette Lemoine , Brigitte Debuire 

Service de Biochimie et Biologie moleculaire, Hopital Paul Brousse, Faculte de Medecine Paris Sud, 94 800 Villejuif, France

Identity

HGNC
LOCATION
18q21.2
IMAGE
Atlas Image
LEGEND
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
LOCUSID
ALIAS
DPC4,JIP,MADH4,MYHRS
FUSION GENES

DNA/RNA

Description

The gene encompasses 49.5 kb of DNA; 13 exons.

Transcription

3220 nucleotides mRNA.

Proteins

Description

552 amino acids; 60.4 kDa protein. Smad4 belongs to the Darfwin family of proteins which harbours two conserved amino- and carboxyl-terminal domains known as MH1 and MH2, respectively. Smad4 in the basal state is found mostly as a homo-oligomer, most likely a trimer.

Expression

Ubiquitous.

Function

Smad4 is an intracellular mediator of TGF-beta family and activin type 1 receptor. Smad4 mediate TGF-beta signaling to regulate cell growth and differentiation. TGF-beta stimulation leads to phosphorylation and activation of Smad2 and Smad3, which form complexes with Smad4 that accumulate in the nucleus and regulate transcription of target genes. By interacting with DNA-binding proteins, Smad complexes then positively or negatively regulate the transcription of target genes.

Homology

With the other members of the Darfwin/Smad family.

Implicated in

Entity name
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Disease
Juvenile polyposis and hereditary hemorrhagic telangiectasia syndrome is an autosomal dominant disorder with distinct clinical features. One form corresponding to a predisposition to gastrointestinal polyps and cancer may be associated with mutations in Smad4 gene.
Oncogenesis
Polyps are formed by inactivation of the Smad4 gene through germline mutations and loss of the unaffected wild-type allele.
Entity name
Pancreatic carcinoma
Disease
90% of pancreatic carcinomas show allelic loss at 18q. A consensus region of homozygous deletion at 18q21.1 was found in one third of pancreatic carcinomas and intragenic mutations were found in another 20% of this tumor type.
Prognosis
Smad4 expression may be a molecular prognostic marker for pancreatic carcinoma. A lower patient survival may be associated with loss of Smad4 expression.
Oncogenesis
Smad4 was proposed to be a tumor suppressor gene that may function to disrupt TGF-beta signaling. Mutant Smad4 proteins, identified in human carcinomas, were found to be impaired in their ability to regulate gene transcription. Most of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2) which interfere with the homo-oligomer formation of Smad4 protein and hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGF-beta signaling.

Bibliography

Pubmed IDLast YearTitleAuthors
103984371999Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients.Friedl W et al
121362442002Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers.Friedl W et al
150310302004A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).Gallione CJ et al
85530701996DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.Hahn SA et al
98119341998Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.Houlston R et al
95454101998A gene for familial juvenile polyposis maps to chromosome 18q21.1.Howe JR et al
95821231998Mutations in the SMAD4/DPC4 gene in juvenile polyposis.Howe JR et al
121914742002Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity.Inman GJ et al
110180292000Distinct oligomeric states of SMAD proteins in the transforming growth factor-beta pathway.Jayaraman L et al
86536891996DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma.Kim SK et al
103403811999Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis.Miyaki M et al
128211122003Role of Smad4 (DPC4) inactivation in human cancer.Miyaki M et al
86536911996DPC4 gene in various tumor types.Schutte M et al
97075531998Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator.Shioda T et al
86731341996Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers.Thiagalingam S et al
104908211999Smad2 and Smad4 gene mutations in hepatocellular carcinoma.Yakicier MC et al
96609451998Human Smad3 and Smad4 are sequence-specific transcription activators.Zawel L et al
94828991998Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells.Zhou S et al

Other Information

Locus ID:

NCBI: 4089
MIM: 600993
HGNC: 6770
Ensembl: ENSG00000141646

Variants:

dbSNP: 4089
ClinVar: 4089
TCGA: ENSG00000141646
COSMIC: SMAD4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000141646ENST00000342988Q13485
ENSG00000141646ENST00000342988A0A024R274
ENSG00000141646ENST00000398417Q13485
ENSG00000141646ENST00000398417A0A024R274
ENSG00000141646ENST00000588745K7EIU8
ENSG00000141646ENST00000588860K7EL18
ENSG00000141646ENST00000589076K7ENG1
ENSG00000141646ENST00000589941K7EL15
ENSG00000141646ENST00000590061K7EIJ2
ENSG00000141646ENST00000592186K7ES96
ENSG00000141646ENST00000593223K7ELK2
ENSG00000141646ENST00000611848A0A087WUF3

Expression (GTEx)

0
5
10
15
20
25
30
35
40

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
Wnt signaling pathwayKEGGko04310
TGF-beta signaling pathwayKEGGko04350
Adherens junctionKEGGko04520
Colorectal cancerKEGGko05210
Pancreatic cancerKEGGko05212
Chronic myeloid leukemiaKEGGko05220
Cell cycleKEGGhsa04110
Wnt signaling pathwayKEGGhsa04310
TGF-beta signaling pathwayKEGGhsa04350
Adherens junctionKEGGhsa04520
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Pancreatic cancerKEGGhsa05212
Chronic myeloid leukemiaKEGGhsa05220
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Hepatitis BKEGGhsa05161
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
FoxO signaling pathwayKEGGhsa04068
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
BMP signalingKEGGhsa_M00679
TGF-beta signalingKEGGhsa_M00680
Activin signalingKEGGhsa_M00681
BMP signalingKEGGM00679
TGF-beta signalingKEGGM00680
Activin signalingKEGGM00681
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by TGF-beta Receptor Complex in CancerREACTOMER-HSA-3304351
Loss of Function of SMAD4 in CancerREACTOMER-HSA-3304347
SMAD4 MH2 Domain Mutants in CancerREACTOMER-HSA-3311021
Loss of Function of SMAD2/3 in CancerREACTOMER-HSA-3304349
SMAD2/3 MH2 Domain Mutants in CancerREACTOMER-HSA-3315487
Signal TransductionREACTOMER-HSA-162582
Signaling by BMPREACTOMER-HSA-201451
Signaling by TGF-beta Receptor ComplexREACTOMER-HSA-170834
TGF-beta receptor signaling activates SMADsREACTOMER-HSA-2173789
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimerREACTOMER-HSA-2173793
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcriptionREACTOMER-HSA-2173796
Downregulation of SMAD2/3:SMAD4 transcriptional activityREACTOMER-HSA-2173795
Signaling by ActivinREACTOMER-HSA-1502540
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Developmental BiologyREACTOMER-HSA-1266738
Signaling by NODALREACTOMER-HSA-1181150
Transcriptional regulation of pluripotent stem cellsREACTOMER-HSA-452723
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
DeubiquitinationREACTOMER-HSA-5688426
Ub-specific processing proteasesREACTOMER-HSA-5689880
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
Apelin signaling pathwayKEGGhsa04371

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
192737102009DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.336
185680182008TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal.246
212896242011SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression.227
161723832005Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway.199
97416231998Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling.183
121914742002Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity.141
195841512009SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer.121
161358022005Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses.116
198415362009Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation.107
125316952003TGF-beta1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins.99

Citation

Raphael Saffroy ; Antoinette Lemoine ; Brigitte Debuire

SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))

Atlas Genet Cytogenet Oncol Haematol. 2004-08-01

Online version: http://atlasgeneticsoncology.org/gene/371/smad4