TGF-beta/Smad Transforming Growth Factor Beta Receptor

The TGF-β signalling pathway is implicated in a variety of cellular processes, including cell proliferation, cell differentiation, apoptosis, migration, and cell fate. The TGF-β signalling pathway is characterized by a superfamily consisting of TGF-β1, TGF-β2, TGF-β3, Activin, Nodals, and bone morphogenetic proteins (BMPs).^[1] Signalling via the TGF-β family occurs through membrane-bound, heteromeric receptor complexes that are made up of two type I and two type II receptor serine-threonine kinases that are activated by TGF-β ligands.^[2] Upon binding of TGF-β the formation of a receptor complex is initiated, enabling constitutively active type II receptors to phosphorylate the glycine and serine-rich region (GS domain) within the type I receptors. Simultaneously, membrane-anchored betaglycan, also known as type III receptor, has been shown to promote ligand binding to the type II receptor. This activity is particularly important for TGF-β2, as it requires betaglycan for high-affinity binding to type II receptor.^[1]

The phosphorylation of the Type I receptor activates the downstream protein, receptor-regulated small and mothers against decapentaplegic (SMAD) protein (R-SMADs, include SMAD1, SMAD2, SMAD3, SMAD5, and SMAD8), through the membrane-bound scaffolding protein, SMAD anchor for receptor activation (SARA), and the adaptor molecule disabled homolog 2 (Dab2). It should be noted that different R-SMADs are activated depending on the pathway of induction. For instance, activation of TGF-β, Nodal or Activin results in the phosphorylation of SMAD2 and SMAD3. In contrast, BMP and growth and differentiation factor (GDF) results in the phosphorylation of SMAD1, SMAD5, and SMAD8. R-SMADs and SMAD4 share a common conserved amino and carboxyl region known as the Mad homology (MH)1 and MH2 domains. In the case of R-SMADs and SMAD4, the MH1 domain contains a nuclear localization signal and DNA-binding activity. Thus, the association of SMAD4 with other R-SMADs and cofactors produces a complex, R-SMAD/SMAD4. This complex then translocates to the nucleus where it binds with low affinity to a DNA sequence called CAGAC, also known as the SMAD-binding element (SBE).^[1]

It should be noted that the R-SMAD/SMAD4 complex can be negatively regulated as well. In this instance, a second SMAD family termed as the inhibitory SMADs (I-SMAD, including SMAD6 and SMAD7) compete with R-SMADs for type I receptor or Co-SMADs. The I-SMADs can also promote the degradation of R-SMADS and co-SMADs by formation of a complex with ubiquitin ligases Smurf1/2.^[1]

In oncology TGF-β signaling plays an important function as both a tumor suppressor and also as an enhancer depending on the state of cells. For instance, in normal and premalignant tissues negative control of the cell cycle produces tumor suppressor functions of TGF-β. Among tumor cells and their surrounding microenvironment, TGF-β is secreted in abundance.^[1] In advanced stages of cancer the downregulation of type II receptor and SMAD4 are observed. In addition, overexpression of SMAD7 and dachshund homolog 1 takes place. The overexpression of these negative regulators of TGF-β implies that suppression of TGF-β is an important event for tumorigenesis to occur. In addition, the overexpression of SMAD3 is associated with increased metastatic potential and poor prognosis.^[1] This stage is also the consequence of TGF-β accumulation into the microenvironment leading to the induction of epithelial-mesenchymal transition (EMT), this is the transition state of epithelial tumors cells to a more aggressive form characterized by invasive behavior, and mesenchymal-like phenotype. Aiding in the process is the expression of cell-cell adhesion molecules and the secretion of metalloproteinases that promote metastasis.^[1] Therefore, dysregulation of TGF-β signalling is likely a result of altered expression of its components.