Biology:Mothers against decapentaplegic homolog 7

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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:

References

  1. ↑ 1.0 1.1 EntrezGene 4092
  2. ↑ "A structural basis for mutational inactivation of the tumour suppressor Smad4". Nature 388 (6637): 87–93. July 1997. doi:10.1038/40431. PMID 9214508. Bibcode: 1997Natur.388R..87S. 
  3. ↑ "Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1". Nature 389 (6651): 618–22. October 1997. doi:10.1038/39348. PMID 9335504. Bibcode: 1997Natur.389..618K. 
  4. ↑ "Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II". Mol. Cell. Biol. 20 (21): 8103–11. November 2000. doi:10.1128/MCB.20.21.8103-8111.2000. PMID 11027280. 
  5. ↑ "Regulation of Smad signaling by protein kinase C". FASEB J. 15 (3): 553–5. March 2001. doi:10.1096/fj.00-0474fje. PMID 11259364. 
  6. ↑ "Transforming growth factor beta1 induces nuclear export of inhibitory Smad7". J. Biol. Chem. 273 (44): 29195–201. October 1998. doi:10.1074/jbc.273.44.29195. PMID 9786930. 
  7. ↑ 7.0 7.1 "The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling". Cell 89 (7): 1165–73. June 1997. doi:10.1016/S0092-8674(00)80303-7. PMID 9215638. 
  8. ↑ "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. May 1999. doi:10.1074/jbc.274.19.13637. PMID 10224135. 
  9. ↑ "Identification of Smad7, a TGFbeta-inducible antagonist of TGF-β signalling". Nature 389 (6651): 631–5. October 1997. doi:10.1038/39369. PMID 9335507. Bibcode: 1997Natur.389..631N. 
  10. ↑ "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. March 2010. doi:10.1016/j.bbrc.2010.02.094. PMID 20171181. 
  11. ↑ "A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA". Genes Dev. 14 (2): 187–97. January 2000. doi:10.1101/gad.14.2.187. PMID 10652273. 
  12. ↑ "Smad7 induces hepatic metastasis in colorectal cancer". Br. J. Cancer 99 (6): 957–65. September 2008. doi:10.1038/sj.bjc.6604562. PMID 18781153. 
  13. ↑ Peterlongo, Paolo, ed (2012). "A common SMAD7 variant is associated with risk of colorectal cancer: evidence from a case-control study and a meta-analysis". PLOS ONE 7 (3): e33318. doi:10.1371/journal.pone.0033318. PMID 22457752. Bibcode: 2012PLoSO...733318S. 
  14. ↑ "The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer". Oncogene 18 (39): 5363–72. September 1999. doi:10.1038/sj.onc.1202909. PMID 10498890. 
  15. ↑ "Yes-associated protein (YAP65) in relation to Smad7 expression in human pancreatic ductal adenocarcinoma". Int. J. Mol. Med. 17 (5): 761–7. May 2006. doi:10.3892/ijmm.17.5.761. PMID 16596258. http://www.spandidos-publications.com/ijmm/17/5/761. 
  16. ↑ "Thioredoxin is downstream of Smad7 in a pathway that promotes growth and suppresses cisplatin-induced apoptosis in pancreatic cancer". Cancer Res. 64 (10): 3599–606. May 2004. doi:10.1158/0008-5472.CAN-03-2999. PMID 15150118. 
  17. ↑ "The Smad family and its role in pancreatic cancer". Indian J Cancer 48 (3): 351–60. 2011. doi:10.4103/0019-509X.84939. PMID 21921337. 
  18. ↑ "Epidermal growth factor-related peptides and their receptors in human malignancies". Crit. Rev. Oncol. Hematol. 19 (3): 183–232. July 1995. doi:10.1016/1040-8428(94)00144-I. PMID 7612182. 
  19. ↑ "An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors". Mol. Cell 12 (3): 541–52. September 2003. doi:10.1016/S1097-2765(03)00350-2. PMID 14527402. 
  20. ↑ "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. June 2009. doi:10.1016/j.cellsig.2009.01.034. PMID 19385051. 
  21. ↑ "Proteinase requirements of epidermal growth factor-induced ovarian cancer cell invasion". Int. J. Cancer 78 (3): 331–7. October 1998. doi:10.1002/(SICI)1097-0215(19981029)78:3<331::AID-IJC13>3.0.CO;2-9. PMID 9766568. 
  22. ↑ "Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells". Cancer Lett. 314 (2): 147–54. January 2012. doi:10.1016/j.canlet.2011.09.024. PMID 22033246. 
  23. ↑ "Phase II Data for Celgene's Investigational Oral GED-0301 for Patients with Active Crohn's Disease Published in New England Journal of Medicine". Celgene Corporation. http://ir.celgene.com/releasedetail.cfm?releaseid=902361. 
  24. ↑ "Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis". Mol. Cell. Biol. 25 (4): 1475–88. February 2005. doi:10.1128/MCB.25.4.1475-1488.2005. PMID 15684397. 
  25. ↑ "Control of Smad7 stability by competition between acetylation and ubiquitination". Mol. Cell 10 (3): 483–93. September 2002. doi:10.1016/S1097-2765(02)00639-1. PMID 12408818. 
  26. ↑ "Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3". Mol. Biol. Cell 14 (2): 529–44. February 2003. doi:10.1091/mbc.02-03-0037. PMID 12589052. 
  27. ↑ "Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7". Genes Cells 6 (12): 1091–9. December 2001. doi:10.1046/j.1365-2443.2001.00483.x. PMID 11737269. 
  28. ↑ "Regulation of transforming growth factor-beta signaling by protein inhibitor of activated STAT, PIASy through Smad3". J. Biol. Chem. 278 (36): 34253–8. September 2003. doi:10.1074/jbc.M304961200. PMID 12815042. http://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/28123/1/JBC278-36.pdf. 
  29. ↑ 29.0 29.1 "Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7". EMBO J. 22 (24): 6458–70. December 2003. doi:10.1093/emboj/cdg632. PMID 14657019. 
  30. ↑ 30.0 30.1 30.2 "STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling". Mol. Cell. Biol. 20 (9): 3157–67. May 2000. doi:10.1128/MCB.20.9.3157-3167.2000. PMID 10757800. 
  31. ↑ "Roles of pathway-specific and inhibitory Smads in activin receptor signaling". Mol. Endocrinol. 13 (1): 15–23. January 1999. doi:10.1210/mend.13.1.0218. PMID 9892009. 
  32. ↑ "Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9314–9. August 1997. doi:10.1073/pnas.94.17.9314. PMID 9256479. Bibcode: 1997PNAS...94.9314T. 
  33. ↑ 33.0 33.1 "Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts". J. Clin. Invest. 113 (2): 253–64. January 2004. doi:10.1172/JCI16269. PMID 14722617. 
  34. ↑ 34.0 34.1 "Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation". Mol. Cell 6 (6): 1365–75. December 2000. doi:10.1016/S1097-2765(00)00134-9. PMID 11163210. 
  35. ↑ "AIMP1/p43 downregulates TGF-beta signaling via stabilization of smurf2". Biochem. Biophys. Res. Commun. 371 (3): 395–400. July 2008. doi:10.1016/j.bbrc.2008.04.099. PMID 18448069. 
  36. ↑ "Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-beta superfamily signaling". J. Biol. Chem. 279 (30): 31568–74. July 2004. doi:10.1074/jbc.M313977200. PMID 15148321. 
  37. ↑ "Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling". Oncogene 21 (32): 4879–84. July 2002. doi:10.1038/sj.onc.1205623. PMID 12118366. http://www.hal.inserm.fr/docs/00/14/74/64/PDF/2002OncogeneYAPSmad7.pdf. 

Further reading



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