1DD1, 1G88, 1MR1, 1U7F, 1U7V, 1YGS, 5MEY, 5MEZ, 5MF0408917128ENSG00000141646ENSMUSG00000024515Q13485P97471NM_005359NM_008540NM_001364967NM_001364968NP_005350NP_032566NP_001351896NP_001351897SMAD4, 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.

Once in the nucleus, the complex of SMAD4 and two R-SMADS binds to DNA and regulates the expression of different genes depending on the cellular context.

[6] Intracellular reactions involving SMAD4 are triggered by the binding, on the surface of the cells, of growth factors from the TGFβ family.

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.

Efficient interactions with GC-sites occur only if a G nucleotide is located deep in the major grove, and establishes hydrogen bonds with the guanidinium group of Arg81.

This interaction facilitates a complementary surface contact between the Smad DNA-binding hairpin and the major groove of the DNA.

The X-ray crystal structure of the Trichoplax adhaerens SMAD4 MH1 domains bound to the GGCGC motif indicates a high conservation of this interaction in metazoans.

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.

SMAD4 serves as a mediator between extracellular growth factors from the TGFβ family and genes inside the cell nucleus.

[17] The FGF (Fibroblast Growth Factor) pathway stimulation leads to Smad4 phosphorylation by Erk of the canonical MAPK site located at Threonine 277.

[18] 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.

These associations are weak and require additional transcription factors such as members of the AP-1 family, TFE3 and FoxG1 to regulate gene expression.

The important number of cell divisions leads to the forming of tumors and then to multiploid colorectal cancer and pancreatic carcinoma.

SMAD 4 is also found mutated in the autosomal dominant disease juvenile polyposis syndrome (JPS).

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.