TGF-β / Smad Signaling

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TGF-β / Smad Signaling

Pathway Description:

Transforming growth factor-β (TGF-β) superfamily signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. In general, signaling is initiated with ligand-induced oligomerization of serine/ threonine receptor kinases and phosphorylation of the cytoplasmic signaling molecules Smad2 and Smad3 for the TGF-β/activin pathway, or Smad1/5/8 for the bone morphogenetic protein (BMP) pathway. Carboxy-terminal phosphorylation of Smads by activated receptors results in their partnering with the common signaling transducer Smad4, and translocation to the nucleus. Activated Smads regulate diverse biological effects by partnering with transcription factors resulting in cell-state specific modulation of transcription. The activin and BMP pathways are themselves attenuated by MAPK signaling at a number of levels, while the expression of inhibitory Smads (I-Smads) 6 and 7 is induced by both activin/TGF-β and BMP signaling as part of a negative feedback loop. In certain contexts, TGF-β signaling can also affect Smad-independent pathways, including Erk, SAPK/JNK, and p38 MAPK pathways. Activation of Smad-independent pathways through TGF-β signaling is also common. Rho GTPase (RhoA) activates downstream target proteins, such as mDia and ROCK, to prompt rearrangement of the cytoskeletal elements associated with cell spreading, cell growth regulation, and cytokinesis. Cdc42/Rac regulates cell adhesion through downstream effector kinases PAK, PKC, and c-Abl following TGF-β activation.

Selected Reviews:

• Herpin A, Cunningham C (2007) Cross-talk between the bone morphogenetic protein pathway and other major signaling pathways results in tightly regulated cell-specific outcomes. FEBS J. 274(12), 2977–85.
• Horbelt D, Denkis A, Knaus P (2012) A portrait of Transforming Growth Factor β superfamily signalling: Background matters. Int. J. Biochem. Cell Biol. 44(3), 469–74.
• Ikushima H, Miyazono K (2010) TGFbeta signalling: a complex web in cancer progression. Nat. Rev. Cancer 10(6), 415–24.
• Kitisin K, Saha T, Blake T, Golestaneh N, Deng M, Kim C, Tang Y, Shetty K, Mishra B, Mishra L (2007) Tgf-Beta signaling in development. Sci. STKE 2007(399), cm1.
• Meulmeester E, Ten Dijke P (2011) The dynamic roles of TGF-β in cancer. J. Pathol. 223(2), 205–18.
• Schmierer B, Hill CS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat. Rev. Mol. Cell Biol. 8(12), 970–82.
• Verheyen EM (2007) Opposing effects of Wnt and MAPK on BMP/Smad signal duration. Dev. Cell 13(6), 755–6.
• Xiao YT, Xiang LX, Shao JZ (2007) Bone morphogenetic protein. Biochem. Biophys. Res. Commun. 362(3), 550–3.

We would like to thank Luuk Hawinkels and Prof. Peter ten Dijke, Leiden University Medical Center, Leiden, The Netherlands, for contributing to this diagram.