Transforming growth factor-β proteins belong to the TGF-β superfamily of cytokines that play a critical role in regulating cell proliferation and differentiation, developmental patterning and morphogenesis, and disease pathogenesis. TGF-β ligands elicit signaling through three cell surface receptors: type I, type II, and type III TGF-β receptors. Type I and type II receptors are serine/threonine kinases that form a heteromeric complex following ligand binding to the type II receptor. In response to ligand binding, the type II receptors form a stable complex with the type I receptors, triggering phosphorylation and activation of the type I receptor. This results in the recruitment of receptor-mediated SMADs, which are phosphorylated by the type I kinase in an SSXS domain in the C-terminus. This leads to recruitment of the co-SMAD, and subsequent translocation of this heteromeric SMAD complex to the nucleus, where it regulates transcription of target genes. The type III receptor, also known as betaglycan, is a transmembrane proteoglycan with a large extracellular domain that binds TGF-β with high affinity but lacks a cytoplasmic signaling domain. Expression of the type III receptor can regulate TGF-β signaling through presentation of the ligand to the signaling complex.There are three TGF-beta family members, designated TGF-β1, TGF-β2, and TGF-β3, which are encoded by distinct genes and are expressed in a tissue specific manner. TGF-β proteins are synthesized as precursor proteins that are cleaved and reassembled in association with other proteins to form latent complexes. Activation occurs by proteolytic release of TGF-β monomers, which dimerize to form the mature TGF-β ligands.
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