It acts as a mediator of the signals initiated by the transforming growth factor beta (TGF-β) superfamily of cytokines, which regulate cell proliferation, differentiation and death.
[7][8] Based on its essential role in TGF beta signaling pathway, SMAD3 has been related with tumor growth in cancer development.
The receptors for TGF-β, (including nodal, activin, myostatin and other family members) are membrane serine/threonine kinases that preferentially phosphorylate and activate SMAD2 and SMAD3.
Once SMAD3 is phosphorylated at the C-terminus, it dissociates from SARA and forms a heterodimeric complex with SMAD4, which is required for the transcriptional regulation of many target genes.
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.
In addition, the three residues strictly conserved in all R-SMADS and in SMAD4 (Arg74 and Gln76 located in β2 and Lys81 in β3 in SMAD3) participate in a network of specific hydrogen bonds with the dsDNA.
The MH2 domain is also a binding platform for cytoplasmic anchors, DNA-binding cofactors, histone modifiers, chromatin readers, and nucleosome- positioning factors.
SMAD3 functions as a transcriptional modulator, binding the TRE (TPA responsive element) in the promoter region of many genes that are regulated by TGF-β.
TGF-β/SMAD signaling pathway has been shown to have a critical role in the expression of genes controlling differentiation of embryonic stem cells.
The c-myc TIE is a composite element, composed of an overlapping RSBE and a consensus E2F site, which is capable of binding at least SMAD3, SMAD4, E2F4, and p107.
Analysis of the relation between SMAD3 and the regulation of angiogenic molecules suggest that SMAD3 may be one of key components as a repressor of the critical angiogenesis switch in prostate cancer.
Studies showed that the overexpression of PTTG1 induces a decrease in SMAD3 expression, promoting the proliferation of prostate cancer cells via the inhibition of SMAD3.
The impact of SMAD3 has also been analyzed in colorectal cancer human cell lines, using single-nucleotide polymorphism (SNP) microarray analysis.
[29] TGF-β-induced SMAD3 transcriptional regulation response has been associated with breast cancer bone metastasis by its effects on tumor angiogenesis, and epithelial-mesenchymal transition (EMT).
There have been identified diverse molecules that act over the TGF-β/SMAD signaling pathway, affecting primarily the SMAD2/3 complex, which have been associated with the development of breast cancer.
The research over FOXM1 suggested that it prevents the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex.
Based on the importance of this molecule, studies have found that FOXM1 is overexpressed in highly aggressive human breast cancer tissues.