Specificity and versatility in TGF-beta signaling through SMADS

Department of Molecular and Cellular Biology, Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Annual Review of Cell and Developmental Biology (Impact Factor: 16.66). 02/2005; 21(1):659-93. DOI: 10.1146/annurev.cellbio.21.022404.142018
Source: PubMed


The TGF-beta family comprises many structurally related differentiation factors that act through a heteromeric receptor complex at the cell surface and an intracellular signal transducing Smad complex. The receptor complex consists of two type II and two type I transmembrane serine/threonine kinases. Upon phosphorylation by the receptors, Smad complexes translocate into the nucleus, where they cooperate with sequence-specific transcription factors to regulate gene expression. The vertebrate genome encodes many ligands, fewer type II and type I receptors, and only a few Smads. In contrast to the perceived simplicity of the signal transduction mechanism with few Smads, the cellular responses to TGF-beta ligands are complex and context dependent. This raises the question of how the specificity of the ligand-induced signaling is achieved. We review the molecular basis for the specificity and versatility of signaling by the many ligands through this conceptually simple signal transduction mechanism.

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    • "The most classical experimental model is the induction of EMT by TGF-β in epithelial cell culture. Upon TGF-β induction, the type II receptor (TGFR2) is activated and phosphorylates the type I receptor (TGFR1), thereby activating the Smad pathway and inducing EMT525354. In the Smad-dependent pathway, TGF-β activates the type II receptor (TGFβRII), resulting in phosphorylation of the type I receptor (TGFβRI), and then activation of Smad3. "
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    • "Contrary to our expectations, no difference in either the kinetics or extent of R-Smad phosphorylation was observed in SNX9 KD or DN clones relative to control (Figures 2, A and B, and Supplemental Figure S1D). Because R-Smad phosphorylation enhances their nuclear accumulation (Feng and Derynck, 2005; Schmierer and Hill, 2007; Hill, 2009), we next investigated whether SNX9 was required for Smad3 nuclear import. While SNX9 loss significantly reduced nuclear Smad3 following addition of TGFβ, nuclear Smad2 was unaffected (Figure 2C). "

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