Smad proteins

Author:Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

SMAD

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DefinitionThis section has been translated automatically.

Group of receptor substrates that control transcription processes in the cell nucleus. The name of the Smad proteins is derived from the genes encoding them, which were first identified in genetic studies on Drosophila and C. elegans. The Drosophila gene is called Mad (Mother against decapentaplegic), the gene in C. elegans is called Sma (Small body size). The combination of these two terms led to the name "Smad".

ClassificationThis section has been translated automatically.

Structurally and functionally there are three subfamilies of the Smad proteins, all of which have a similar, strongly conserved basic sequence:
  • Receptor Smad proteins (Smad 2 and 3)
  • Cooperative Smad proteins (Co-Smads, Smad 4)
  • Inhibitory Smad proteins (Smad 6 and 7).

General informationThis section has been translated automatically.

All Smad proteins are relatively similar in structure. The highly conserved chain ends are connected by a linker of variable length and sequence. The N-terminus of Smad 4, the so-called MH1 domain, fulfils the function of binding to DNA promoters after activation and translocation into the cell nucleus. The C-terminal MH2 domain can bind to various proteins, for example to type 1 receptors, to other Smads and to transcription factors. After phosphorylation, the Smad complex permeates into the cell nucleus where it enters into interactions with transcription factors via the MH2 domain of R-Smads or directly mediates gene expression by binding from the MH1 domain of Smad 4 to promoters. Smad complexes also appear to have an inhibitory effect on DNA segments of growth-promoting genes such as c-myc.

The so-called receptor-Smad proteins (Smad 2 and Smad 3) bind to the receptor complex and are phosphorylated by the type 1 receptor. The phosphorylated R-Smad proteins form a complex with the cooperative Smad 4, which is able to penetrate the cell nucleus. Here the activated R-Smads attach themselves to DNA promoters and/or transcription factors and control transcription processes.

The inhibitory Smad proteins (Smad 6 and Smad 7) antagonize the attachment of the R-Smads to the receptor complex or to Smad 4. The receptor Smad proteins (R-Smads, Smad 2 and 3) interact directly with the type 1 receptor activated by the mechanisms described above. Only after phosphorylation can R-Smads bind the cytoplasmic cooperative Smad proteins (Co-Smads, Smad 4), which ultimately serve to attach the Smad complex to DNA promoters and to activate transcription.

The third group are the inhibitory Smad proteins (I-Smads, Smad 6 and 7). They are characterized by striking structural variations in comparison to the R- and Co-Smads. This is due to the fact that they competitively antagonize the TGF-mediated signal transduction. Both I-Smads are increasingly formed as a result of a large supply of growth factors, thus serving as negative feedback. They can compete with the R-Smads for receptor binding as well as prevent the interaction of R-Smad and Co-Smad.

The Activin Responsive Factor (ARF) can be cited for the combination of Smad proteins with transcription factors. This can interact with the activin responsive element (ARE) at the Mix2 gene only after cooperation with the Smad complex.

With the increasing establishment of the knock-out procedure and its application also to Smad proteins and TGF-β it became possible to observe the effects of the absence of these signal molecules on the orderly skin development. In this procedure, which specifically switches off genes for certain proteins, the blastocyst, which forms after natural fertilization, is removed and transfected with foreign DNA. The DNA is imported by transfer by retrovirus or microinjection. The embryonic cells are then implanted into a surrogate mother and their development is observed. The added DNA, which automatically passes from the cytoplasm into the cell nucleus, contains a segment that exactly corresponds to the gene to be eliminated. This segment attaches itself to the target sequence in the course of homologous recombination and fuses with it at the superposition site. Since the entire carrier structure is incorporated into the gene, transcription and the resulting protein synthesis are no longer possible.

LiteratureThis section has been translated automatically.

  1. Ashcroft GS et al (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1: 260-266
  2. Denton CP et al (2001) Transforming growth factor-beta and connective tissue growth factor: key cytokines in scleroderma pathogenesis. Curr Opin Rheumatol 13: 505-511
  3. Holmes A et al (2001) CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem 276: 10594-10601
  4. Dong C et al (2002) Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci USA 99: 3908-3913
  5. Itoh S et al (2000) Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem 267: 6954-6967
  6. Massague J (1998) TGF-β signal transduction. Ann Rev Biochem 67: 753-791
  7. Mori Y et al (2003) Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum 48: 1964-1978
  8. Takagawa S et al (2003) Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. J Invest Dermatol 121: 41-50
  9. Yang X et al (1999) Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness toTGF-β. EMBO J 18: 1280-1291

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Last updated on: 29.10.2020