TGF-β Signaling

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• Pathway Key
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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 feed-back 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:

• Attisano L, Wrana JL (2002) Signal transduction by the TGF-beta superfamily. Science 296(5573), 1646–7.
• Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958), 577–84.
• Inman GJ, Nicolás FJ, Hill CS (2002) Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-β receptor activity. Mol. Cell 10(2), 283–94.
• Kretzschmar M, Doody J, Massagué J (1997) Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389(6651), 618–22.
• Massagué J (2000) How cells read TGF-β signals. Nat. Rev. Mol. Cell Biol. 1(3), 169–78.
• Massagué J, Chen YG (2000) Controlling TGF-beta signaling. Genes Dev. 14(6), 627–44.

CST would like to thank Prof. Rik Derynck, University of California at San Francisco, California, for contributing to this diagram.

created January 2003 • revised January 2007