Transforming growth factor-β
Transforming growth factor-β (TGF-β) is the prototypical member of a family of cytokines that play vital roles in processes ranging from embryonic patterning, organ development, immune regulation, and tissue homeostasis. TGF-β was initially identified as one of a family of polypeptides isolated from transformed cells that could peomote anchorage-independent growth of normal rat kidney fibroblasts. This transforming ability was later used as a biological activity assay to purify TGF-β from human placenta. TGF-β exists as a disulfide-linked dimer of two identical 13 kDa(112 amino acid) subunits that are synthesized as 390 amino acid precursor polypeptides and cleaved to give rise to the mature cytokine. Since the initial discovery and cloning of TGF-β (now known as TGF-β1), four additional isoforms of the cytokine have been identified in mammals, although only TGF-β1, TGF-β2, and TGF-β3 have been extensively studies. Other members of the TGF-β cytokine family include Nodal, activin, bone morphogenic protein (BMP), and Mullerian inhibiting substance.This genetic evidence that the Smad proteins are downstream of the receptors was supported by biochemical characterization of the Smad signal transduction pathway. Ectopically expressed mammalian Smad2 was reported to transiently interact with the TGF-β receptor complex, become phosphorylated in response to TGF-β stimulation, and translocate to the nucleus after phosphorylation. After cloning of human Smad2, it was found that the endogenous protein is phosphorylated and translocates to the nucleus in response to TGF-β stimulation. Similar observations were made with Smad3, which is highly homologous to Smad2 and Smad3 in TGF-β signal transduction came with the observation that either protein could potentiate the transcriptional response to TGF-β stimulation.
The Smad proteins can be classified in three categories based on their function in the signaling pathway. Receptor Smads (R-Smads) are the Smad proteins that are phosphorylated by the type I receptor. The R-Smads are further classified based on the their involvement in the signaling pathways of specific TGF-β family members. Smad1, Smad5, and Smad8 are involved in BMP signal transduction, whereas Smad2 and Smad3 are involved in TGF-β and activin signal transduction. A second category of Smads, the inhibitory Smad (I-Smads), includes Smad6 and Smad7, which act to antagonize TGF-β signaling. The third class of Smads is the common Smad, Smad4, which participates in signaling by all TGF-β family members. An important role Smad4 in TGF-β family signaling was suggested by the observation that Smad4 is required for TGF-β-induced growth arrest in mammalian cells and activin-induced mesodermal induction in xenopus. in biochemical experiments, it was found that TGF-β induces the association of phosphorylated Smad2 or Smad3 with Smad4.The R-Smads and Smad4 share sequence homology in two domains: the Mad homology 1 (MH1) and Mad honology 2 (MH2) domain. In Smad4 and in phosphorylated R-Smads, the MH1 domain has DNA binding activity. The MH2 domain contains receptor phosphorylation sites in the R-Smads, and also possesses transactivation activity and sites for protein-protein interactions. In the basal state, the MH1 domain of R-Smads participates in an intramolecular interaction with the MH2 domain and inhibits its function. The I-Smads contain only the MH2 domain, which is sufficient for their inhibitory function.
Conery, A. R. (2005). Regulation of TGF-beta-induced apoptosis by the serine/threonine kinase Akt/protein kinase B.
Products for TGF-beta/Smad