Mothers against decapentaplegic homolog 4

Source: Wikipedia, the free encyclopedia.

SMAD4
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000141646

ENSMUSG00000024515

UniProt

Q13485

P97471

RefSeq (mRNA)

NM_005359

NM_008540
NM_001364967
NM_001364968

RefSeq (protein)

NP_005350

NP_032566
NP_001351896
NP_001351897

Location (UCSC)Chr 18: 51.03 – 51.09 MbChr 18: 73.77 – 73.84 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 (Deleted in Pancreatic Cancer-4) is a highly conserved protein present in all

metazoans. It belongs to the SMAD family of transcription factor proteins, which act as mediators of TGF-β signal transduction. The TGFβ family of cytokines regulates critical processes during the lifecycle of metazoans, with important roles during embryo development, tissue homeostasis, regeneration, and immune regulation.[5]

SMAD 4 belongs to the

Darwin family of proteins that modulate members of the TGFβ protein superfamily, a family of proteins that all play a role in the regulation of cellular responses. Mammalian SMAD4 is a homolog of the Drosophila protein "Mothers against decapentaplegic" named Medea.[6]

SMAD4 interacts with R-Smads, such as

TGFβ
family. The sequence of intracellular reactions involving SMADS is called the SMAD pathway or the transforming growth factor beta (TGF-β) pathway since the sequence starts with the recognition of TGF-β by cells.

Gene

In mammals, SMAD4 is coded by a gene located on chromosome 18. In humans, the SMAD4 gene contains 54 829 base pairs and is located from pair n° 51,030,212 to pair 51,085,041 in the region 21.1 of the chromosome 18.[7][8]

Pattern of the chromosome 18 in Homo sapiens. The SMAD 4 gene is located on the long arm of the chromosome, at locus 21.1. This locus corresponds to the black stripe between the regions 12.3 and 21.2.

Protein

SMAD4 is a 552 amino-acid

Da. SMAD4 has two functional domains known as MH1 and MH2
.

SMAD 4 is composed of three major domains, including MH1 (up), MH2 (down) and a linking domain (right).

The complex of two SMAD3 (or of two SMAD2) and one SMAD4 binds directly to DNA though interactions of their MH1 domains. These complexes are recruited to sites throughout the genome by cell lineage-defining transcription factors (LDTFs) that determine the context-dependent nature of TGF-β action. Early insights into the DNA binding specificity of Smad proteins came from oligonucleotide binding screens, which identified the palindromic duplex 5'–GTCTAGAC–3' as a high affinity binding sequence for SMAD3 and SMAD4 MH1 domains.[9] Other motifs have also been identified in promoters and enhancers. These additional sites contain the CAGCC motif and the GGC(GC)|(CG) consensus sequences, the latter also known as 5GC sites.[10] The 5GC-motifs are highly represented as clusters of sites, in SMAD-bound regions genome-wide. These clusters can also contain CAG(AC)|(CC) sites. SMAD3/SMAD4 complex also binds to the TPA-responsive gene promoter elements, which have the sequence motif TGAGTCAG.[11]

Structures

MH1 domain complexes with DNA motifs

The first structure of SMAD4 bound to DNA was the complex with the palindromic GTCTAGAC motif.

Trichoplax adhaerens SMAD4 MH1 domains bound to the GGCGC motif indicates a high conservation of this interaction in metazoans.[10]

Smad4 MH1 domain bound to the GGCT DNA motif, from PDB: 5MEZ​
Close-up view of the Smad4 MH1 domain bound to the GGCGC DNA motif, from PDB: 5MEY​
Smad4 MH1 domain bound to the GGCGC DNA motif, from PDB: 5MEY​

MH2 domain complexes

The MH2 domain, corresponding to the

heterodimers and heterotrimers. Some tumor mutations detected in SMAD4 enhance interactions between the MH1 and MH2 domains.[13]

Nomenclature and origin of name

SMADs are highly conserved across species, especially in the

C terminal MH2 domain
. The SMAD proteins are homologs of both the Drosophila protein MAD and the C. elegans protein SMA. The name is a combination of the two. During Drosophila research, it was found that a mutation in the gene MAD in the mother repressed the gene decapentaplegic in the embryo. The phrase "Mothers against" was added, since mothers often form organizations opposing various issues, e.g. Mothers Against Drunk Driving (MADD), reflecting "the maternal-effect enhancement of dpp";[14] and based on a tradition of unusual naming within the research community.[15] SMAD4 is also known as DPC4, JIP or MADH4.

Function and action mechanism

SMAD4 is a protein defined as an essential effector in the SMAD pathway. SMAD4 serves as a mediator between extracellular growth factors from the TGFβ family and genes inside the cell nucleus. The abbreviation co in co-SMAD stands for common mediator. SMAD4 is also defined as a signal transducer.

In the TGF-β pathway, TGF-β dimers are recognized by a transmembrane receptor, known as type II receptor. Once the type II receptor is activated by the binding of TGF-β, it phosphorylates a type I receptor. Type I receptor is also a

heteromeric
complex. This complex is going to move from the cytoplasm to the nucleus: it is the translocation. SMAD4 may form heterotrimeric, heterohexameric or heterodimeric complexes with R-SMADS.

SMAD4 is a substrate of the

colon cancer progression.[20]

In the nucleus the heteromeric complex binds promoters and interact with transcriptional activators.

AP-1 family, TFE3 and FoxG1 to regulate gene expression.[21]

Many TGFβ ligands use this

embryonic development and the cell cycle
.

Clinical significance

Genetic experiments such as

Mus musculus
).

It has been shown that, in mouse KO of SMAD4, the

bone morphogenetic protein-7 effects as BMP-7 uses the SMAD4 signaling pathway.[22][23]

Deletions in the genes coding for SMAD1 and

SMAD5 have also been linked to metastasic granulosa cell tumors in mice.[24]

SMAD4, is often found mutated in many cancers. The mutation can be inherited or acquired during an individual's lifetime. If inherited, the mutation affects both

fibroblasts
. The functional SMAD 4 participates in the regulation of the TGF-β signal transduction pathway, which negatively regulates growth of epithelial cells and the
pancreatic carcinoma. It is found inactivated in at least 50% of pancreatic cancers.[25]

Somatic mutations found in human cancers of the MH1 domain of SMAD 4 have been shown to inhibit the DNA-binding function of this domain.

SMAD 4 is also found mutated in the

colon cancer
. Around 60 mutations causing JPS have been identified. They have been linked to the production of a smaller SMAD 4, with missing domains that prevent the protein from binding to R-SMADS and forming
heteromeric complexes.[8]

Mutations in SMAD4 (mostly substitutions) can cause Myhre syndrome, a rare inherited disorder characterized by mental disabilities, short stature, unusual facial features, and various bone abnormalities.[26][27]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000141646 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024515 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 22992590
    .
  6. ^
    PMID 9759503
    .
  7. ^ "SMAD4 SMAD family member 4". Entrez Gene.
  8. ^ a b "SMAD 4". The Genetics Home Reference Website.
  9. PMID 9660945
    .
  10. ^
    PMID 29234012
    .
  11. S2CID 4393852
    .
  12. PMID 21724602
    .
  13. S2CID 4407819
    .
  14. PMID 7768443
    .
  15. ^ White M (26 September 2014). "Sonic Hedgehog, DICER, and the Problem With Naming Genes". Pacific Standard.
  16. S2CID 9326115
    .
  17. PMID 25373906
    .
  18. PMID 10636916
    .
  19. PMID 27308623
    .
  20. PMID 27308538
    .
  21. PMID 15702493
    .
  22. PMID 19108831
    .
  23. PMID 16513794
    .
  24. PMID 19819941
    .
  25. ISBN 0-7216-0187-1
    .
  26. ^ "Growth-Mental Deficiency Syndrome of Myhre". National Organization for rare disorders. Archived from the original on 2 April 2015. Retrieved 26 March 2015.
  27. S2CID 5294309
    .

Further reading

External links
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