Mothers against decapentaplegic homolog 7 orSMAD7 is aprotein that in humans is encoded by theSMAD7gene.[5]
SMAD7 is a protein that, as its name describes, is a homolog of theDrosophila gene: "Mothers against decapentaplegic". It belongs to theSMAD family of proteins, which belong to theTGFβ superfamily of ligands. Like many other TGFβ family members, SMAD7 is involved incell signalling. It is a TGFβ type 1receptor antagonist. It blocksTGFβ1 and activin associating with the receptor, blocking access toSMAD2. It is an inhibitory SMAD (I-SMAD) and is enhanced bySMURF2.
Smad proteins contain two conserved domains. The Mad Homology domain 1 (MH1 domain) is at theN-terminal and the Mad Homology domain 2 (MH2 domain) is at theC-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.[6] The linker region contains important regulatory peptide motifs including potentialphosphorylation sites for mitogen-activated protein kinases(MAPKs), Erk-family MAP kinases,[7] the Ca2+ /calmodulin-dependent protein kinase II (CamKII)[8] andprotein kinase C (PKC).[9] 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 E3ubiquitin ligase, the Smad ubiquitination-related factors (Smurf2). It resides predominantly in the nucleus at basal state and translocates to thecytoplasm upon TGF-β stimulation.[10]
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.[11] By occupying type I receptors forActivin andbone morphogenetic protein (BMP), it also plays a role innegative feedback of these pathways.[12][13]
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 theIRAK1-mediatedIL-1R/TLR signaling complex therefore abrogates NF-κB activity, which subsequently causes reduced expression of pro-inflammatory genes.[14]
While Smad7 is induced by TGF-β, it is also induced by other stimuli, such asepidermal 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.[15]
A mutation located in SMAD7 gene is a cause of susceptibility tocolorectal cancer (CRC) type 3.[5] Perturbation of Smad7 and suppression of TGF-β signaling was found to be evolved in CRC.[16] Case control studies andmeta-analysis in Asian and European populations also provided evidence that this mutation is associated with colorectal cancer risk.[17]
TGF-β is one of the important growth factors inpancreatic 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[18][19][20] but there was a recent study showed a low Smad7 expression. The role of Smad7 in pancreatic cancer is still controversial.[21]
Over-expression or constitutive activation ofepidermal growth factor receptor (EGFR) can promote tumor processes.[22][23] EGF-inducedMMP-9 expression enhances tumor invasion andmetastasis in some kinds of tumor cells such asbreast cancer andovarian cancer.[24][25] Smad7 exerts an inhibitory effect on the EGF signaling pathway. Therefore, it may play a role in prevention of cancer metastasis.[26]
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.[27]
^Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P (October 1997). "Identification of Smad7, a TGFbeta-inducible antagonist of TGF-β signalling".Nature.389 (6651):631–5.Bibcode:1997Natur.389..631N.doi:10.1038/39369.PMID9335507.S2CID4311145.
^Lee YS, Kim JH, Kim ST, Kwon JY, Hong S, Kim SJ, Park SH (March 2010). "Smad7 and Smad6 bind to discrete regions of Pellino-1 via their MH2 domains to mediate TGF-beta1-induced negative regulation of IL-1R/TLR signaling".Biochem. Biophys. Res. Commun.393 (4):836–43.Bibcode:2010BBRC..393..836L.doi:10.1016/j.bbrc.2010.02.094.PMID20171181.
^Salomon DS, Brandt R, Ciardiello F, Normanno N (July 1995). "Epidermal growth factor-related peptides and their receptors in human malignancies".Crit. Rev. Oncol. Hematol.19 (3):183–232.doi:10.1016/1040-8428(94)00144-I.PMID7612182.
^Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Cho S, Kim JS, Kim JH, Choe JH, Nam SJ, Lee JE, Yang JH (June 2009). "EGF-induced MMP-9 expression is mediated by the JAK3/ERK pathway, but not by the JAK3/STAT-3 pathway in a SKBR3 breast cancer cell line".Cell. Signal.21 (6):892–8.doi:10.1016/j.cellsig.2009.01.034.PMID19385051.
^Kim S, Han J, Lee SK, Koo M, Cho DH, Bae SY, Choi MY, Kim JS, Kim JH, Choe JH, Yang JH, Nam SJ, Lee JE (January 2012). "Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells".Cancer Lett.314 (2):147–54.doi:10.1016/j.canlet.2011.09.024.PMID22033246.
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.PMID10647776.
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.PMID9730599.S2CID46753315.
