The transforming growth factor β (TGF-β) family of hormones plays a crucial role in regulating cellular functions during animal development and tissue homeostasis. TGF-β signaling is mediated through a relatively simple system involving membrane receptors and Smad proteins, which transmit signals to the nucleus to regulate gene expression. This system is highly regulated, with various mechanisms controlling the access of TGF-β family members to their receptors, the activity of receptors and their substrates, and the nuclear function of transcriptional complexes. These regulatory mechanisms are as intricate and physiologically important as those downstream of the receptors. The TGF-β family includes several subfamilies, such as the bone morphogenetic proteins (BMPs), Activin, and Nodal, each with distinct roles in development and tissue homeostasis. The signaling pathway involves two receptor serine/threonine kinases (receptor types I and II) and Smad proteins, which form complexes that regulate gene expression. The type I receptor, in its basal state, is inactive due to a wedge-shaped structure that dislocates its catalytic center. Upon ligand binding, the type II receptor phosphorylates the GS region, activating the type I receptor, which then phosphorylates Smad proteins. These Smad proteins, known as R-Smads, associate with co-Smads (Smad4 or Smad4β) to regulate gene expression. The specificity of receptor-Smad interactions is determined by specific loops and domains on the receptors and Smads. The R-Smads and co-Smads have conserved domains that allow them to bind DNA and interact with cofactors, which determine the final transcriptional outcome. The choice of target genes by an activated Smad complex is influenced by the association with specific DNA-binding cofactors, which can vary depending on the cell type and the signaling context. The TGF-β family's signaling pathways are regulated by various ligand-binding proteins that prevent ligand access to receptors, contributing to the formation of morphogen gradients and the homeostasis of signaling inputs. The latent TGF-β is synthesized as a prohormone and is cleaved into an active form, which is then regulated by latent TGF-β-binding proteins (LTBPs). The activation of latent TGF-β involves a complex process, with various proteins such as thrombospondin-1 and integrin αvβ6 playing important roles. Follistatin is a soluble secreted glycoprotein that suppresses Activin signaling by binding to Activin and inhibiting its interaction with receptors. It also binds to BMPs and can induce neural tissue in Xenopus embryos. BMP antagonists such as Noggin and Chordin are secreted proteins that inhibit BMP signaling by blocking BMP interaction with cell-surface receptors. These proteins are crucial for proper embryonic development and tissue patterning. The DAN family of BMP antagonists includes proteins suchThe transforming growth factor β (TGF-β) family of hormones plays a crucial role in regulating cellular functions during animal development and tissue homeostasis. TGF-β signaling is mediated through a relatively simple system involving membrane receptors and Smad proteins, which transmit signals to the nucleus to regulate gene expression. This system is highly regulated, with various mechanisms controlling the access of TGF-β family members to their receptors, the activity of receptors and their substrates, and the nuclear function of transcriptional complexes. These regulatory mechanisms are as intricate and physiologically important as those downstream of the receptors. The TGF-β family includes several subfamilies, such as the bone morphogenetic proteins (BMPs), Activin, and Nodal, each with distinct roles in development and tissue homeostasis. The signaling pathway involves two receptor serine/threonine kinases (receptor types I and II) and Smad proteins, which form complexes that regulate gene expression. The type I receptor, in its basal state, is inactive due to a wedge-shaped structure that dislocates its catalytic center. Upon ligand binding, the type II receptor phosphorylates the GS region, activating the type I receptor, which then phosphorylates Smad proteins. These Smad proteins, known as R-Smads, associate with co-Smads (Smad4 or Smad4β) to regulate gene expression. The specificity of receptor-Smad interactions is determined by specific loops and domains on the receptors and Smads. The R-Smads and co-Smads have conserved domains that allow them to bind DNA and interact with cofactors, which determine the final transcriptional outcome. The choice of target genes by an activated Smad complex is influenced by the association with specific DNA-binding cofactors, which can vary depending on the cell type and the signaling context. The TGF-β family's signaling pathways are regulated by various ligand-binding proteins that prevent ligand access to receptors, contributing to the formation of morphogen gradients and the homeostasis of signaling inputs. The latent TGF-β is synthesized as a prohormone and is cleaved into an active form, which is then regulated by latent TGF-β-binding proteins (LTBPs). The activation of latent TGF-β involves a complex process, with various proteins such as thrombospondin-1 and integrin αvβ6 playing important roles. Follistatin is a soluble secreted glycoprotein that suppresses Activin signaling by binding to Activin and inhibiting its interaction with receptors. It also binds to BMPs and can induce neural tissue in Xenopus embryos. BMP antagonists such as Noggin and Chordin are secreted proteins that inhibit BMP signaling by blocking BMP interaction with cell-surface receptors. These proteins are crucial for proper embryonic development and tissue patterning. The DAN family of BMP antagonists includes proteins such