Mothers against decapentaplegic homolog 7
An Error has occurred retrieving Wikidata item for infobox Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the SMAD7 gene.[1]
SMAD7 is a protein that, as its name describes, is a homolog of the Drosophila gene: "Mothers against decapentaplegic". It belongs to the SMAD family of proteins, which belong to the TGFβ superfamily of ligands. Like many other TGFβ family members, SMAD7 is involved in cell signalling. It is a TGFβ type 1 receptor antagonist. It blocks TGFβ1 and activin associating with the receptor, blocking access to SMAD2. It is an inhibitory SMAD (I-SMAD) and is enhanced by SMURF2.
Smad7 enhances muscle differentiation.
Structure
Smad proteins contain two conserved domains. The Mad Homology domain 1 (MH1 domain) is at the N-terminal and the Mad Homology domain 2 (MH2 domain) is at the C-terminal. Between them there is a linker region which is full of regulatory sites. The MH1 domain has DNA binding activity while the MH2 domain has transcriptional activity.[2] The linker region contains important regulatory peptide motifs including potential phosphorylation sites for mitogen-activated protein kinases(MAPKs), Erk-family MAP kinases,[3] the Ca2+ /calmodulin-dependent protein kinase II (CamKII)[4] and protein kinase C (PKC).[5] Smad7 does not have the MH1 domain. A proline-tyrosine (PY) motif presents at its linker region enables its interaction with the WW domains of the E3 ubiquitin ligase, the Smad ubiquitination-related factors (Smurf2). It resides predominantly in the nucleus at basal state and translocates to the cytoplasm upon TGF-β stimulation.[6]
Function
SMAD7 inhibits TGF-β signaling by preventing formation of Smad2/Smad4 complexes which initiate the TGF-β signaling. It interacts with activated TGF-β type I receptor therefore block the association, phosphorylation and activation of Smad2.[7] By occupying type I receptors for Activin and bone morphogenetic protein (BMP), it also plays a role in negative feedback of these pathways.[8][9]
Upon TGF- β treatment, Smad7 binds to discrete regions of Pellino-1 via distinct regions of the Smad MH2 domains. The interaction blocks the formation of the IRAK1-mediated IL-1R/TLR signaling complex therefore abrogates NF-κB activity, which subsequently causes reduced expression of pro-inflammatory genes.[10]
While Smad7 is induced by TGF-β, it is also induced by other stimuli, such as epidermal growth factor (EGF), interferon-γ and tumor necrosis factor (TNF)-α. Therefore, it provides a cross-talk between TGF-β signaling and other cellular signaling pathways.[11]
Role in cancer
A mutation located in SMAD7 gene is a cause of susceptibility to colorectal cancer (CRC) type 3.[1] Perturbation of Smad7 and suppression of TGF-β signaling was found to be evolved in CRC.[12] Case control studies and meta-analysis in Asian and European populations also provided evidence that this mutation is associated with colorectal cancer risk.[13]
TGF-β is one of the important growth factors in pancreatic cancer. By controlling the TGF-β pathway, smad7 is believed to be related to this disease. Some previous study showed over-expression of Smad7 in pancreatic cells[14][15][16] but there was a recent study showed a low Smad7 expression. The role of Smad7 in pancreatic cancer is still controversial.[17]
Over-expression or constitutive activation of epidermal growth factor receptor (EGFR) can promote tumor processes.[18][19] EGF-induced MMP-9 expression enhances tumor invasion and metastasis in some kinds of tumor cells such as breast cancer and ovarian cancer.[20][21] Smad7 exerts an inhibitory effect on the EGF signaling pathway. Therefore, it may play a role in prevention of cancer metastasis.[22]
Use in Pharmacology
SMAD7 signaling has been studied in a recent Celgene Phase III trial, NCT ID number 94, which interacts with the SMAD7 pathway. This drug (Mongersen) was studied in patients with Crohn's disease.[23]
Interactions
Mothers against decapentaplegic homolog 7 has been shown to interact with:
- CTNNB1,[24]
- EP300,[25]
- TAB1,[26][27]
- PIAS4,[28]
- RNF111,[29]
- SMAD3.[30][31]
- SMAD6,[32]
- SMURF2,[33][34][35]
- STRAP,[30]
- TGFBR1,[7][29][30][33][34][36] and
- YAP1.[37]
References
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Further reading
- Massagué J (1998). "TGF-beta signal transduction". Annu. Rev. Biochem. 67: 753–91. doi:10.1146/annurev.biochem.67.1.753. PMID 9759503.
- Verschueren K, Huylebroeck D (1999). "Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells". Cytokine Growth Factor Rev. 10 (3–4): 187–99. doi:10.1016/S1359-6101(99)00012-X. PMID 10647776.
- Wrana JL, Attisano L (2000). "The Smad pathway". Cytokine Growth Factor Rev. 11 (1–2): 5–13. doi:10.1016/S1359-6101(99)00024-6. PMID 10708948.
- Miyazono K, ten Dijke P, Heldin CH (2000). "TGF-β signaling by Smad proteins". TGF-beta signaling by Smad proteins. Adv. Immunol. Advances in Immunology. Vol. 75. pp. 115–157. doi:10.1016/S0065-2776(00)75003-6. ISBN 9780120224753. PMID 10879283.
- Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA, Wrana JL, Falb D (June 1997). "The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling". Cell. 89 (7): 1165–73. doi:10.1016/S0092-8674(00)80303-7. PMID 9215638. S2CID 16552782.
- Röijer E, Morén A, ten Dijke P, Stenman G (1998). "Assignment1 of the Smad7 gene (MADH7) to human chromosome 18q21.1 by fluorescence in situ hybridization". Cytogenet. Cell Genet. 81 (3–4): 189–90. doi:10.1159/000015026. PMID 9730599. S2CID 46753315.
- Denissova NG, Pouponnot C, Long J, He D, Liu F (June 2000). "Transforming growth factor beta -inducible independent binding of SMAD to the Smad7 promoter". Proc. Natl. Acad. Sci. U.S.A. 97 (12): 6397–402. Bibcode:2000PNAS...97.6397D. doi:10.1073/pnas.090099297. PMC 18614. PMID 10823886.
- Stopa M, Anhuf D, Terstegen L, Gatsios P, Gressner AM, Dooley S (September 2000). "Participation of Smad2, Smad3, and Smad4 in transforming growth factor beta (TGF-beta)-induced activation of Smad7. THE TGF-beta response element of the promoter requires functional Smad binding element and E-box sequences for transcriptional regulation". J. Biol. Chem. 275 (38): 29308–17. doi:10.1074/jbc.M003282200. PMID 10887185.
- Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K (April 2001). "Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation". J. Biol. Chem. 276 (16): 12477–80. doi:10.1074/jbc.C100008200. PMID 11278251.
- Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (August 2001). "Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads". EMBO J. 20 (15): 4132–42. doi:10.1093/emboj/20.15.4132. PMC 149146. PMID 11483516.