The TGF-β/Smad signaling system is a key regulator of gene expression in multicellular organisms. This system involves a family of membrane receptor protein kinases and a family of receptor substrates, the Smad proteins, which act as transcription factors upon entering the nucleus. TGF-β ligands assemble a receptor complex that activates Smads, which then form multisubunit complexes that regulate transcription. The system is controlled by a web of regulatory proteins that ensure precise and context-dependent signaling. Smad proteins are divided into subfamilies, including R-Smads (receptor-activated Smads) and Co-Smads (co-Smads). R-Smads are activated by phosphorylation and then associate with Co-Smads to form transcriptional complexes. These complexes bind to DNA sequences called SBEs (Smad-binding elements) and regulate gene expression. The specificity of Smad interactions with their target genes is determined by structural elements on the type I receptors and R-Smads, such as the L45 loop and the L3 loop. Smad proteins also interact with other transcription factors, such as FAST and OAZ, which provide additional specificity and regulate gene expression. These interactions are crucial for determining the cellular context and the specific genes that are activated or repressed. Smad proteins can also act as coactivators or corepressors, working with other transcription factors to modulate gene expression. The TGF-β signaling pathway is involved in various biological processes, including cell proliferation, differentiation, and apoptosis. The regulation of this pathway is complex and involves multiple layers of control, including the interaction of Smads with other transcription factors, the recruitment of coactivators or corepressors, and the modulation of Smad activity by various signaling pathways. The study of the TGF-β/Smad signaling system has revealed the importance of context-dependent regulation in gene expression. The ability of Smads to bind to DNA and regulate transcription is influenced by the presence of specific DNA sequences, the interaction with other transcription factors, and the availability of coactivators or corepressors. Understanding these mechanisms is essential for elucidating the role of TGF-β signaling in development, disease, and other biological processes.The TGF-β/Smad signaling system is a key regulator of gene expression in multicellular organisms. This system involves a family of membrane receptor protein kinases and a family of receptor substrates, the Smad proteins, which act as transcription factors upon entering the nucleus. TGF-β ligands assemble a receptor complex that activates Smads, which then form multisubunit complexes that regulate transcription. The system is controlled by a web of regulatory proteins that ensure precise and context-dependent signaling. Smad proteins are divided into subfamilies, including R-Smads (receptor-activated Smads) and Co-Smads (co-Smads). R-Smads are activated by phosphorylation and then associate with Co-Smads to form transcriptional complexes. These complexes bind to DNA sequences called SBEs (Smad-binding elements) and regulate gene expression. The specificity of Smad interactions with their target genes is determined by structural elements on the type I receptors and R-Smads, such as the L45 loop and the L3 loop. Smad proteins also interact with other transcription factors, such as FAST and OAZ, which provide additional specificity and regulate gene expression. These interactions are crucial for determining the cellular context and the specific genes that are activated or repressed. Smad proteins can also act as coactivators or corepressors, working with other transcription factors to modulate gene expression. The TGF-β signaling pathway is involved in various biological processes, including cell proliferation, differentiation, and apoptosis. The regulation of this pathway is complex and involves multiple layers of control, including the interaction of Smads with other transcription factors, the recruitment of coactivators or corepressors, and the modulation of Smad activity by various signaling pathways. The study of the TGF-β/Smad signaling system has revealed the importance of context-dependent regulation in gene expression. The ability of Smads to bind to DNA and regulate transcription is influenced by the presence of specific DNA sequences, the interaction with other transcription factors, and the availability of coactivators or corepressors. Understanding these mechanisms is essential for elucidating the role of TGF-β signaling in development, disease, and other biological processes.