Mothers against decapentaplegic homolog 7 or SMAD7 is a
protein that in humans is encoded by the SMAD7gene.[5]
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.[6] The linker region contains important regulatory peptide motifs including potential
phosphorylation sites for mitogen-activated protein kinases(
MAPKs), Erk-family MAP kinases,[7] the Ca2+ /calmodulin-dependent protein kinase II (CamKII)[8] and
protein 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 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.[10]
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.[11] By occupying type I receptors for
Activin and
bone morphogenetic protein (BMP), it also plays a role in
negative 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 the
IRAK1-mediated
IL-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 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.[15]
Role in cancer
A mutation located in SMAD7 gene is a cause of susceptibility to
colorectal 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 and
meta-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 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[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 of
epidermal growth factor receptor (EGFR) can promote tumor processes.[22][23] EGF-induced
MMP-9 expression enhances tumor invasion and
metastasis in some kinds of tumor cells such as
breast cancer and
ovarian 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]
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.[27]
Interactions
Mothers against decapentaplegic homolog 7 has been shown to
interact with:
^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.
doi:
10.1016/j.bbrc.2010.02.094.
PMID20171181.
^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.
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.