Mothers against decapentaplegic homolog 4

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SMAD family member 4
Protein SMAD4 PDB 1dd1.png
PDB rendering based on 1dd1.
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM600993 MGI894293 HomoloGene31310 GeneCards: SMAD4 Gene
RNA expression pattern
PBB GE SMAD4 202527 s at tn.png
PBB GE SMAD4 202526 at tn.png
More reference expression data
Species Human Mouse
Entrez 4089 17128
Ensembl ENSG00000141646 ENSMUSG00000024515
UniProt Q13485 P97471
RefSeq (mRNA) NM_005359 NM_008540
RefSeq (protein) NP_005350 NP_032566
Location (UCSC) Chr 18:
51.03 – 51.09 Mb
Chr 18:
73.64 – 73.7 Mb
PubMed search [1] [2]

SMAD 4, also called SMAD family member n°4 or Mothers against decapentaplegic homolog 4, is a protein involved in cell signaling in mammals. It belongs to the proteins of the SMAD family.

SMAD 4 participates in chain reactions inside cells where it interacts with other members of the SMAD family such as SMAD2 or SMAD3. SMAD 4 forms with SMAD 3 a complex which can bind to DNA and modify the expression of several genes related to cellular activities such as proliferation or differentiation.[1] The complex SMAD 3-SMAD 4 is therefore a transcription factor. Intracellular reactions involving SMAD 4 are triggered by the binding, on the surface of the cells, of growth factors from the 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.

SMAD 4 belongs to the co-SMAD group, the second class of the SMAD family. SMAD 4 is the only known co-SMAD in mammals. It also 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 SMAD 4 is a homolog of the Drosophila protein "Mothers against decapentaplegic" or MAD.


SMAD family member 4 is a 552 amino-acid polypeptide with a molecular weight of 60 439 daltons. This protein is composed of only one chain of amino acids.

SMAD 4 is always coded in mammals by a gene located on chromosome 18. In humans, the protein is coded by the SMAD 4 gene, which is located in the region 21.1 of chromosome 18.[2] The human gene contains 54 829 base pairs and is located from pair n° 51,030,212 to pair 51,085,041.[3]


SMAD 4 has a tri-dimensional structure and two functional domains known as MH1 and MH2. The letters M and H stand for MAD Homology and refer to the similarity between mammals SMAD 4 and the Drosophilia protein Mothers against decapentaplegic (MAD).[4]


The MH1 domain, corresponding to the N-terminus, contains amino-acids with physical and chemical properties that give SMAD 4 specific DNA-binding properties. This region recognizes a specific DNA sequence composed of eight nucleotides: G-T-C-T-A-G-A-C.[5]

The sequence is also recognized by SMAD 3, which forms a protein complex with SMAD 4 in the cytoplasm of mammalian cells. It is therefore sometimes called the "consensus sequence" but is mostly known as Smad-binding DNA element (SBE). The MH1 domain facilitates the binding of SMAD 4 to receptors such as SMAD 2 and SMAD 3 which belong to the R-SMAD group (first class of the SMAD family) by interacting with their phosphorylated MH2 domain.

The MH2 domain, corresponding to the C-terminus, is responsible for receptor recognition, DNA binding and association with other SMADs. Just as the MH1 domain interacts with the R-SMADS MH2 domain, the SMAD 4 MH2 domain directly interacts with their MH1 domain.[4] SMAD 4 can therefore form with other SMADS heterodimers and heterotrimers.

Nomenclature and origin of name[edit]


SMAD 4 is also known as DPC4, JIP or MADH4.

Function and action mechanism[edit]

SMAD 4 is a protein defined as an essential effector in the SMAD pathway. SMAD 4 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. SMAD 4 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 cell surface receptor. This receptor then phosphorylates intracellular receptor regulated SMADS (R-SMADS) such as SMAD 2 or SMAD 3. The phosphorylated R-SMADS then bind to SMAD 4. The R-SMADs-SMAD 4 association is 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 Erk/MAPK kinase [7] and GSK3.[8] The FGF (Fibroblast Growth Factor) pathway stimulation leads to Smad4 phosphorylation by Erk of the canonical MAPK site located at Threonine 277. This phosphorylation event has a dual effect on Smad4 activity. First, it allows Smad4 to reach its peak of transcriptional activity by activating a growth factor-regulated transcription activation domain located in the Smad4 linker region, SAD (Smad-Activation Domain).[9] Second, MAPK primes Smad4 for GSK3-mediated phosphorylations that cause transcriptional inhibition and also generate a phosphodegron used as a docking site by the ubiquitin E3 ligase Beta-transducin Repeat Containing (beta-TrCP) that polyubiquitinates Smad4 and targets it for degradation in the proteasome.[10] Smad4 GSK3 phosphorylations have been proposed to regulate the protein stability during pancreatic and colon cancer progression.[11]



Clinical significance[edit]









  1. ^ Lin X, Liang M, Liang YY, Brunicardi FC, Melchior F, Feng XH (May 2003). "Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4". The Journal of Biological Chemistry 278 (21): 18714–18719. doi:10.1074/jbc.M302243200. PMID 12621041. 
  2. ^ "SMAD4 SMAD family member 4". Entrez Gene. 
  3. ^ a b "SMAD 4". The Genetics Home Reference Website. 
  4. ^ a b Roelen BA, Cohen OS, Raychowdhury MK, Chadee DN, Zhang Y, Kyriakis JM, Alessandrini AA, Lin HY (Oct 2003). "Phosphorylation of threonine 276 in Smad4 is involved in transforming growth factor-beta-induced nuclear accumulation". American Journal of Physiology. Cell Physiology 285 (4): C823–30. doi:10.1152/ajpcell.00053.2003. PMID 12801888. 
  5. ^ Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B, Kern SE (Mar 1998). "Human Smad3 and Smad4 are sequence-specific transcription activators". Molecular Cell 1 (4): 611–617. doi:10.1016/s1097-2765(00)80061-1. PMID 9660945. 
  6. ^ Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM (Mar 1995). "Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster" (PDF). Genetics 139 (3): 1347–58. PMC 1206461. PMID 7768443. 
  8. ^ Demagny H, Araki T, De Robertis EM (Oct 2014). "The tumor suppressor Smad4/DPC4 is regulated by phosphorylations that integrate FGF, Wnt, and TGF-β signaling". Cell Reports 9 (2): 688–700. doi:10.1016/j.celrep.2014.09.020. PMID 25373906. 
  9. ^ de Caestecker, Mark P. "The Smad4 Activation Domain (SAD) Is a Proline-rich, p300-dependent Transcriptional Activation Domain". The Journal of Biological Chemistry 275: 2115–2122. doi:10.1074/jbc.275.3.2115. 
  10. ^ Demagny H, De Robertis EM. "Smad4/DPC4: a Barrier against Tumor Progression driven by RTK/Ras/Erk and Wnt/GSK3 signaling". Molecular & Cellular Oncology: e989133. doi:10.4161/23723556.2014.989133. 
  11. ^ Demagny H, De Robertis EM. "Point Mutations in the Tumor Suppressor Smad4/DPC4 Enhance its Phosphorylation by GSK3 and Reversibly Inactivate TGF-β Signaling.". Molecular & Cellular Oncology 3: e1025181. doi:10.1080/23723556.2015.1025181. 
  12. ^ Inman GJ (Feb 2005). "Linking Smads and transcriptional activation". The Biochemical Journal 386 (Pt 1): e1–e3. doi:10.1042/bj20042133. PMC 1134782. PMID 15702493. 
  13. ^ Shi J, Yoshino O, Osuga Y, Nishii O, Yano T, Taketani Y (Mar 2010). "Bone morphogenetic protein 7 (BMP-7) increases the expression of follicle-stimulating hormone (FSH) receptor in human granulosa cells". Fertility and Sterility 93 (4): 1273–9. doi:10.1016/j.fertnstert.2008.11.014. PMID 19108831. 
  14. ^ Pangas SA, Li X, Robertson EJ, Matzuk MM (Jun 2006). "Premature luteinization and cumulus cell defects in ovarian-specific Smad4 knockout mice". Molecular Endocrinology 20 (6): 1406–22. doi:10.1210/me.2005-0462. PMID 16513794. 
  17. ^ "Growth-Mental Deficiency Syndrome of Myhre". National Organization for rare disorders. 
  18. ^ Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M (Jul 2014). "Novel SMAD4 mutation causing Myhre syndrome". American Journal of Medical Genetics. Part A 164A (7): 1835–40. doi:10.1002/ajmg.a.36544. PMID 24715504. 

Further reading[edit]

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