The abbreviation refers to the homologies to the Caenorhabditis elegans SMA ("small" worm phenotype) and MAD family ("Mothers Against Decapentaplegic") of genes in Drosophila.
R/Co-Smads are primarily located in the cytoplasm, but accumulate in the nucleus following TGF-β signaling, where they can bind to DNA and regulate transcription.
These globular regions are highly conserved in R-Smads and Co-Smads, and are called Mad homology 1 (MH1) at the N-terminus, and MH2 at the C-terminus.
The MH1 domain is primarily involved in DNA binding, while the MH2 is responsible for the interaction with other Smads and also for the recognition of transcriptional co-activators and co-repressors.
Indeed, the different phosphorylation patterns generated by CDK8/9 and GSK3 define the specific interactions with either transcription activators or with ubiquitin ligases.
[18][19] Remarkably, the linker region has the highest concentration of amino acid differences among metazoans, although the phosphorylation sites and the PY motif are highly conserved.
The components of the TGF-beta pathway and in particular, the R-Smads, Co-Smad and I-Smads, are represented in the genome of all metazoans sequenced to date.
[23] This phosphorylation event activates the type 1 receptors, making them capable of further propagating the TGF-B signal via Smads.
[24] Phosphorylation of the R-Smad causes it to dissociate from SARA, exposing a nuclear import sequence, as well as promoting its association with a Co-Smad.
In addition, the I-Smad recruits a ubiquitin ligase to target the activate R-Smad for degradation, effectively silencing the TGF-β signal.
[28] This phenomenon is present in the epithelial cells of many organs, and is regulated in part by the Smad signaling pathway.
One mechanism by which Smads facilitate TGF-β induced cytostasis is by downregulating Myc, which is a transcription factor that promotes cell growth.
TGF-B signal triggers Smad3 phosphorylation, which in turn activates ATF3, a transcription factor that is induced during cellular stress.
However, depleting Smad2 in a similar manner enhanced, rather than halted, TGF-B induced cell cycle arrest.
[37] Germline Smad4 mutations are partially responsible for genetic disposition for human familial juvenile polyposis, which puts a person at high risk of developing potentially cancerous gastrointestinal polyps.
Experimental supporting evidence for this observation comes from a study showing that heterozygous Smad4 knockout mice (+/-) uniformly developed gastrointestinal polyps by 100 weeks.
[38] Many familial Smad4 mutants occur on the MH2 domain, which disrupts the protein's ability to form homo- or hetero-oligomers, thus impairing TGF-B signal transduction.
Research has shown that phosphorylated Smad2 is ectopically localized to cytoplasmic granules rather than the nucleus, in hippocampal neurons of patients with Alzheimer's disease.
[43] Recent studies show that the peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is involved in promoting the abnormal localization of Smad2.
In the kidneys, TGF-B1 promotes accumulation of the extracellular matrix (ECM) by increasing its production and inhibiting its degradation, which is characteristic of renal fibrosis.
[46] Smad3 knockout mice display reduced progression of renal fibrosis, suggesting its importance in regulating the disease.
This loss of TGF-B inhibition results in increased amounts of active Smad2/3, which contribute to the progression of renal fibrosis as described above.