Mothers against decapentaplegic homolog 7

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SMAD family member 7
SMURF2 SMAD7 complex.png
Solution Structure Of Smurf2 Ww3 Domain-Smad7 Py Peptide Complex
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SMAD7 ; CRCS3; MADH7; MADH8
External IDs OMIM602932 MGI1100518 HomoloGene4314 GeneCards: SMAD7 Gene
RNA expression pattern
PBB GE SMAD7 204790 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4092 17131
Ensembl ENSG00000101665 ENSMUSG00000025880
UniProt O15105 O35253
RefSeq (mRNA) NM_001190821 NM_001042660
RefSeq (protein) NP_001177750 NP_001036125
Location (UCSC) Chr 18:
46.45 – 46.48 Mb
Chr 18:
75.37 – 75.4 Mb
PubMed search [1] [2]

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[edit]

Smads 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 do 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 by TGF-β stimulation.[6]

Function[edit]

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[edit]

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 factor 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 enhance 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 EGF signaling pathway. Therefore it may play a role in prevention of cancer metastasis.[22]

Interactions[edit]

Mothers against decapentaplegic homolog 7 has been shown to interact with:

References[edit]

  1. ^ a b EntrezGene 4092
  2. ^ Shi Y, Hata A, Lo RS, Massagué J, Pavletich NP (July 1997). "A structural basis for mutational inactivation of the tumour suppressor Smad4". Nature 388 (6637): 87–93. doi:10.1038/40431. PMID 9214508. 
  3. ^ Kretzschmar M, Doody J, Massagué J (October 1997). "Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1". Nature 389 (6651): 618–22. doi:10.1038/39348. PMID 9335504. 
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  6. ^ Itóh S, Landström M, Hermansson A, Itoh F, Heldin CH, Heldin NE, ten Dijke P (October 1998). "Transforming growth factor beta1 induces nuclear export of inhibitory Smad7". J. Biol. Chem. 273 (44): 29195–201. doi:10.1074/jbc.273.44.29195. PMID 9786930. 
  7. ^ a b 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. 
  8. ^ Ishisaki A, Yamato K, Hashimoto S, Nakao A, Tamaki K, Nonaka K, ten Dijke P, Sugino H, Nishihara T (May 1999). "Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells". J. Biol. Chem. 274 (19): 13637–42. doi:10.1074/jbc.274.19.13637. PMID 10224135. 
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  18. ^ 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. PMID 7612182. 
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Further reading[edit]