SMAD (protein)

SMADs are intracellular proteins that transduce extracellular signals from transforming growth factor beta ligands to the nucleus where they activate downstream TGF-β gene transcription.[1][2][3][4][5][6]

The SMADs, which form a trimer of two receptor-regulated SMADs and one co-SMAD, act as transcription factors that regulate the expression of certain genes.[7][8]



There are three classes of SMAD:

  1. The receptor-regulated Smads (R-SMAD) which include SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8/9[9]
  2. The common-mediator Smad (co-SMAD) which includes only SMAD4, which interacts with R-SMADs to participate in signaling[10]
  3. The antagonistic or inhibitory Smads (I-SMAD) which include SMAD6 and SMAD7, which block the activation of R-SMADs and Co-SMADs.[11]


The SMAD proteins are homologs of both the drosophila protein, mothers against decapentaplegic (MAD) and the Caenorhabditis elegans protein SMA. The name is a combination of the two.

During Drosophila research, it was found that a mutation in the gene, MAD, in the mother, repressed the gene decapentaplegic in the embryo.


  1. ^ Heldin CH, Miyazono K, ten Dijke P (December 1997). "TGF-beta signalling from cell membrane to nucleus through SMAD proteins". Nature 390 (6659): 465–71. doi:10.1038/37284. PMID 9393997. 
  2. ^ Attisano L, Wrana JL (April 1998). "Mads and Smads in TGF beta signalling". Curr. Opin. Cell Biol. 10 (2): 188–94. doi:10.1016/S0955-0674(98)80141-5. PMID 9561843. 
  3. ^ Massagué J (1998). "TGF-beta signal transduction". Annu. Rev. Biochem. 67: 753–91. doi:10.1146/annurev.biochem.67.1.753. PMID 9759503. 
  4. ^ Attisano L, Wrana JL (May 2002). "Signal transduction by the TGF-beta superfamily". Science 296 (5573): 1646–7. doi:10.1126/science.1071809. PMID 12040180. 
  5. ^ Whitman M (August 1998). "Smads and early developmental signaling by the TGFbeta superfamily". Genes Dev. 12 (16): 2445–62. doi:10.1101/gad.12.16.2445. PMID 9716398. 
  6. ^ Wrana JL (March 2000). "Crossing Smads". Sci. STKE 2000 (23): RE1. doi:10.1126/stke.2000.23.re1. PMID 11752591. 
  7. ^ Derynck R, Zhang Y, Feng XH (December 1998). "Smads: transcriptional activators of TGF-beta responses". Cell 95 (6): 737–40. doi:10.1016/S0092-8674(00)81696-7. PMID 9865691. 
  8. ^ Massagué J, Seoane J, Wotton D (December 2005). "Smad transcription factors". Genes Dev. 19 (23): 2783–810. doi:10.1101/gad.1350705. PMID 16322555. 
  9. ^ Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R, Massagué J, Shi Y (December 2001). "Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling". Mol. Cell 8 (6): 1277–89. doi:10.1016/S1097-2765(01)00421-X. PMID 11779503. 
  10. ^ 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. 
  11. ^ 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. 

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