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.