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TGF-ß SIGNAL TRANSDUCTION IN ORO-FACIAL HEALTH AND NON-MALIGNANT DISEASE (PART I)

Department of Oral and Dental Science, Division of Oral Medicine, Pathology and Microbiology, Bristol Dental Hospital and School, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, UK;

View larger version (61K): [in a new window]   Figure 1. TGF-ß receptor activation. TGF-ß initiates signaling by the assembly of receptor complexes involving two transmembrane serine-threonine kinase receptors (TßR-I and TßR-II). Following binding of TGF-ß to TßR-II, TßR-I is recruited to form a heterotetrameric complex and is phosphorylated at serine residues within its GS domain by the constitutively active TßR-II. The activated TßR-I then activates a cascade of downstream signaling events that ultimately regulates gene transcription.

View larger version (30K): [in a new window]   Figure 2. Structure of Smad proteins. The R and Co-Smads show considerable homology within both the MH1 and MH2 domains. The MH domains are separated by a variable proline-rich linker region, which, in the case of Smad4, contains a Smad activation domain (SAD). **Smad2 is unable to bind directly to DNA, due to a 30-amino-acid insertion within exon3 of the MH1 domain. I-Smads have C-terminal domains structurally similar to R and Co-Smads. The N-terminus, however, fails to show significant homology.

View larger version (49K): [in a new window]   Figure 3. Smad signaling. The activated TßR-I kinase phosphorylates the R-Smads, Smad2 and Smad3, which then form heterodimers with the Co-Smad, Smad4. The complex translates to the nucleus and regulates gene transcription by binding directly to DNA via interactions with DNA-binding proteins and/or transcriptional co-activators and co-repressors. The transcription of the I-Smad, Smad7, is induced, and Smad7 exits the nucleus to control the intensity and duration of signaling via a negative feedback mechanism.

View larger version (43K): [in a new window]   Figure 4. Cellular effects of TGF-ß. TGF-ß is a multi-functional cytokine that inhibits epithelial cell growth, induces apoptosis in a variety of cell types, stimulates new vessel growth, and is a potent immunosuppressant. In addition, TGF-ß functions to elaborate the extracellular matrix.