Smad-dependent and Smad-independent pathways in TGF-β family signalling


Transforming growth factor-β (TGF-β) proteins regulate cell function, and have key roles in development and carcinogenesis. The intracellular effectors of TGF-β signalling, the Smad proteins, are activated by receptors and translocate into the nucleus, where they regulate transcription. Although this pathway is inherently simple, combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smad-interacting proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF-β family responses. Other signalling pathways further regulate Smad activation and function. In addition, TGF-β receptors activate Smad-independent pathways that not only regulate Smad signalling, but also allow Smad-independent TGF-β responses.

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Figure 1: General mechanism of TGF-β receptor and Smad activation.
Figure 2: Combinatorial interactions of type II and type I receptors define the signalling responses.
Figure 3: Structural organization and role of the domains of Smads, and candidate target sites for kinase pathways.
Figure 4: R-Smad activation is regulated by receptor-interacting proteins and Smad6/Smad7.
Figure 5: The R-Smad–Smad4 complex cooperates with sequence-specific transcription factors (X) that bind with high affinity to a cognate DNA sequence (XBE), yet also binds with lower affinity to a Smad-binding DNA element (SBE) to activate transcription in response to TGF-β ligand.
Figure 6: TGF-β receptor signalling through Smad-independent pathways.


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Derynck, R., Zhang, Y. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425, 577–584 (2003).

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