Mothers against decapentaplegic homolog 3
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Location (UCSC) | Chr 15: 67.06 – 67.2 Mb | Chr 9: 63.55 – 63.67 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.[5][6]
SMAD3 is a member of the SMAD family of proteins. 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.
Gene
The human SMAD3 gene is located on
The expression of SMAD3 has been related to the mitogen-activated protein kinase (MAPK/ERK pathway), particularly to the activity of mitogen-activated protein kinase kinase-1 (MEK1).[10] Studies have demonstrated that inhibition of MEK1 activity also inhibits SMAD3 expression in epithelial cells and smooth muscle cells, two cell types highly responsive to TGF-β1.[10]
Protein
SMAD3 is a
Once SMAD3 is phosphorylated at the C-terminus, it dissociates from SARA and forms a heterodimeric complex with
Transcriptional coregulators, such as WWTR1 (TAZ), interact with SMAD3 to promote their function.
Structure
MH1 domain
The X-ray structures of the SMAD3 MH1 domain bound to the GTCT DNA reveal characteristic features of the fold. The MH1 structure consists of four-helices and three sets of antiparallel β-hairpins, one of which is used to interact with DNA. It also revealed the presence of a bound Zn2+, coordinated by His126, Cys64, Cys109 and Cys121 residues.[11][12] The main DNA binding region of the MH1 domain comprises the loop following the β1 strand, and the β2-β3 hairpin. In the complex with a member of the 5GC DNAs, the GGCGC motif, the convex face of the DNA-binding hairpin dives into the concave major groove of the duplex DNA containing five base pairs (GGCGC /'GCGCC'). 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. Several tightly bound water molecules at the protein-DNA interface that contribute to the stabilization of the interactions have also been detected. The SMAD3 complex with the GGCGC site reveals that the protein-DNA interface is highly complementary and that one MH1 protein covers a DNA binding site of six base pairs.
MH2 domain
The MH2 domain mediates the interaction of R-SMADS with activated TGF-β receptors, and with SMAD4 after receptor-mediated phosphorylation of the Ser-X-Ser motif present in R-SMADS. The MH2 domain is also a binding platform for cytoplasmic anchors, DNA-binding cofactors, histone modifiers, chromatin readers, and nucleosome- positioning factors. The structure of the complex of SMAD3 and SMAD4 MH2 domains has been determined.[14] The MH2 fold is defined by two sets of antiparallel β-strands (six and five strands respectively) arranged as a β-sandwich flanked by a triple-helical bundle on one side and by a set of large loops and a helix on the other.
Functions and interactions
TGF-β/SMAD signaling pathway
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. SMAD3 and SMAD4 can also form a complex with
TGF-β/SMAD3-induced repression
Besides the activity of TGF-β in the up-regulation of genes, this signaling molecule also induces the repression of target genes containing the TGF-β inhibitory element (TIE).
Clinical significance
Diseases
Increased SMAD3 activity has, however, been implicated in the pathogenesis of scleroderma.
SMAD3 is also a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes. SMAD3-knockout mice have diminished
Role in cancer
The role of SMAD3 in the regulation of genes important for cell fate, such as differentiation, growth and death, implies that an alteration in its activity or repressing of its activity can lead to the formation or development of cancer. Also several studies have proven the bifunctional tumor suppressor/oncogene role of TGF beta signaling pathway in carcinogenesis.[22]
One way in which SMAD3 transcriptional activator function is repressed, is by the activity of EVI-1.
Prostate
The activity of SMAD3 in prostate cancer is related with the regulation of angiogenic molecules expression in tumor vascularization and cell-cycle inhibitor in tumor growth.[24][25] The progressive growth of primary tumors and metastases in prostate cancer depends on an adequate blood supply provided by tumor angiogenesis. Studies analyzing SMAD3 levels of expression in prostate cancer cell lines found that the two androgen-independent and androgen receptor-negative cell lines (PC-3MM2 and DU145) have high expression levels of SMAD3. 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.[25] The pituitary tumor-transforming gene 1 (PTTG1) has also an impact in SMAD3-mediated TGFβ signaling. PTTG1 has been associated with various cancer cells including prostate cancer cells. 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.[24]
Colorectal
In mice, mutation of SMAD3 has been linked to colorectal adenocarcinoma,[3] increased systemic inflammation, and accelerated wound healing.[4] Studies have shown that mutations in SMAD3 gene promote colorectal cancer in mice.[26][27][28] The altered activity of SMAD3 was linked to chronic inflammation and somatic mutations that contribute to chronic colitis and the development of colorectal cancer.[28] The results generated on mice helped identify SMAD3 like a possible player in human colorectal cancer. The impact of SMAD3 has also been analyzed in colorectal cancer human cell lines, using single-nucleotide polymorphism (SNP) microarray analysis. The results showed reductions in SMAD3 transcriptional activity and SMAD2-SMAD4 complex formation, underlining the critical roles of these three proteins within the TGF-β signaling pathway and the impact of this pathway in colorectal cancer development.[29]
Breast
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.[30]
FOXM1 (forkhead box M1) is a molecule that binds with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. 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. FOXM1 is a key player in the activity of the SMAD3/SMAD4 complex, promoting SMAD3 modulator transcriptional activity, and also plays an important role in the turnover of the activity of SMAD3/SMAD4 complex. Based on the importance of this molecule, studies have found that FOXM1 is overexpressed in highly aggressive human breast cancer tissues. The results from these studies also found that the FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG.[31]
MED15 is a mediator molecule that promotes the activity of the TGF-β/SMAD signaling. The deficiency of this molecule attenuates the activity of the TGF-β/SMAD signaling pathway over the genes required for induction of epithelial-mesenchymal transition. The action of MED15 is related with the phosphorylation of SMAD2/3 complex. The knockdown of MED15 reduces the amount of SMAD3 phosphorylated, therefore reducing its activity as transcription modulator. However, in cancer, MED15 is also highly expressed in clinical breast cancer tissues correlated with hyperactive TGF-β signaling, as indicated by SMAD3 phosphorylation. The studies suggest that MED15 increases the metastatic potential of a breast cancer cell line by increasing TGF-β-induced epithelial–mesenchymal transition.[32]
Kidney
Smad3 activation plays a role in the pathogenesis of renal fibrosis,
Nomenclature
The SMAD proteins are homologs of both the Drosophila protein "mothers against decapentaplegic" (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 inspired by organizations formed by mothers to oppose social problems, such as Mothers Against Drunk Driving (MADD); and based on a tradition of such unusual naming within the gene research community.[35]
A reference assembly of SMAD3 is available.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000166949 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032402 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: SMAD3 SMAD family member 3".
- S2CID 4306019.
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- ^ GeneCards. "SMAD3 Gene".
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- ^ White M (14 June 2017). "The Problem With Naming Genes". Pacific Standard. Retrieved 2022-09-27.
Further reading
- Tan CK, Chong HC, Tan EH, Tan NS (March 2012). "Getting 'Smad' about obesity and diabetes". Nutrition & Diabetes. 2 (3): e29. PMID 23449528.
- Li H, Liu JP (October 2007). "Mechanisms of action of TGF-beta in cancer: evidence for Smad3 as a repressor of the hTERT gene". Annals of the New York Academy of Sciences. 1114 (1): 56–68. S2CID 83825009.
- Matsuzaki K (June 2006). "Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis". Histology and Histopathology. 21 (6): 645–662. PMID 16528675.
- Miyazono K (2000). "TGF-beta signaling by Smad proteins". Cytokine & Growth Factor Reviews. 11 (1–2): 15–22. PMID 10708949.
- Wrana JL, Attisano L (2000). "The Smad pathway". Cytokine & Growth Factor Reviews. 11 (1–2): 5–13. PMID 10708948.
- Verschueren K, Huylebroeck D (2000). "Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells". Cytokine & Growth Factor Reviews. 10 (3–4): 187–199. PMID 10647776.
- Massagué J (1998). "TGF-beta signal transduction". Annual Review of Biochemistry. 67: 753–791. PMID 9759503.
- Walker LC, Waddell N, Ten Haaf A, Grimmond S, Spurdle AB (November 2008). "Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers". Breast Cancer Research and Treatment. 112 (2): 229–236. S2CID 795870.
- Lee KB, Jeon JH, Choi I, Kwon OY, Yu K, You KH (February 2008). "Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability". Biochemical and Biophysical Research Communications. 366 (4): 905–909. PMID 18082619.
- Kim TD, Shin S, Janknecht R (February 2008). "Repression of Smad3 activity by histone demethylase SMCX/JARID1C". Biochemical and Biophysical Research Communications. 366 (2): 563–567. PMID 18078810.
- Zhao X, Nicholls JM, Chen YG (February 2008). "Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-beta signaling". The Journal of Biological Chemistry. 283 (6): 3272–3280. S2CID 84455415.
- Li T, Chiang JY (November 2007). "A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene". Gastroenterology. 133 (5): 1660–1669. PMID 17920062.
- Lu S, Lee J, Revelo M, Wang X, Lu S, Dong Z (October 2007). "Smad3 is overexpressed in advanced human prostate cancer and necessary for progressive growth of prostate cancer cells in nude mice". Clinical Cancer Research. 13 (19): 5692–5702. S2CID 14496617.
- Kalo E, Buganim Y, Shapira KE, Besserglick H, Goldfinger N, Weisz L, et al. (December 2007). "Mutant p53 attenuates the SMAD-dependent transforming growth factor beta1 (TGF-beta1) signaling pathway by repressing the expression of TGF-beta receptor type II". Molecular and Cellular Biology. 27 (23): 8228–8242. PMID 17875924.
- Weng HL, Ciuclan L, Liu Y, Hamzavi J, Godoy P, Gaitantzi H, et al. (October 2007). "Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes". Hepatology. 46 (4): 1257–1270. S2CID 43285490.
- Dennler S, André J, Alexaki I, Li A, Magnaldo T, ten Dijke P, et al. (July 2007). "Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo" (PDF). Cancer Research. 67 (14): 6981–6986. S2CID 46238797.
- Zhang M, Lee CH, Luo DD, Krupa A, Fraser D, Phillips A (September 2007). "Polarity of response to transforming growth factor-beta1 in proximal tubular epithelial cells is regulated by beta-catenin". The Journal of Biological Chemistry. 282 (39): 28639–28647. S2CID 41791801.
- Martin MM, Buckenberger JA, Jiang J, Malana GE, Knoell DL, Feldman DS, et al. (September 2007). "TGF-beta1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways". American Journal of Physiology. Lung Cellular and Molecular Physiology. 293 (3): L790–L799. PMID 17601799.
- Dai F, Chang C, Lin X, Dai P, Mei L, Feng XH (September 2007). "Erbin inhibits transforming growth factor beta signaling through a novel Smad-interacting domain". Molecular and Cellular Biology. 27 (17): 6183–6194. PMID 17591701.
- Levy L, Howell M, Das D, Harkin S, Episkopou V, Hill CS (September 2007). "Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation". Molecular and Cellular Biology. 27 (17): 6068–6083. PMID 17591695.
- Jeon HY, Pornour M, Ryu H, Khadka S, Xu R, Jang J, et al. (Apr 2023). "SMAD3 promotes expression and activity of the androgen receptor in prostate cancer". Nucleic Acids Research. 51 (6): 2655–2670. PMID 36727462.