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g fgrowth factorTransforming growth factor beta From Wikipedia, the free encyclopedia Transforming growth factor beta (TGF-β) is a protein that controls proliferation, cellular differentiation, and other functions in most cells. It is a type of cytokine which plays a role in immunity, cancer, heart disease, diabetes, Marfan syndrome, Loeys–Dietz syndrome, Parkinsons Disease and AIDS. TGF-β is a secreted protein that exists in at least three isoforms called TGF-β1, TGF-β2 and TGF-β3. It was also the original name for TGF-β1, which was the founding member of this family. The TGF-β family is part of a superfamily of proteins known as the transforming growth factor beta superfamily, which includes inhibins, activin, anti-müllerian hormone, bone morphogenetic protein, decapentaplegic and Vg-1. TGF-beta acts as an antiproliferative factor in normal epithelial cells and at early stages of oncogenesis.[1] Some cells that secrete TGF-β also have receptors for TGF-β. This is known as autocrine signalling. Cancerous cells increase their production of TGF-β, which also acts on surrounding cells. TGF-beta is secreted by many cell types, including macrophages, in a latent form in which it is complexed with two other polypeptides, latent TGF-beta binding protein (LTBP) and latency-associated peptide (LAP). Serum proteinases such as plasmin catalyze the release of active TGF-beta from the complex. This often occurs on the surface of macrophages where the latent TGF-beta complex is bound to CD36 via its ligand, thrombospondin-1 (TSP-1). Inflammatory stimuli that activate macrophages enhance the release of active TGF-beta by promoting the activation of plasmin. Macrophages can also endocytose IgG-bound latent TGF-beta complexes that are secreted by plasma cells and then release active TGF-beta into the extracellular fluid.[2] Contents 1 The Structure of TGF-β 2 Function 2.1 Apoptosis 2.1.1 SMAD pathway 2.1.2 DAXX pathway 2.2 Cell cycle 2.3 Immune System 3 Clinical significance 3.1 Cancer 3.2 Heart disease 3.3 Marfan Syndrome 3.4 Loeys–Dietz syndrome 3.5 Other 4 Types 5 TGF-β activation 6 TGF-β latency (latent TGF-β complex) 7 Integrin-independent TGF-β activation 8 Activation by Alpha(V) containing integrins The Structure of TGF-β The peptide structures of the three members of the TGF-β family are highly similar. They are all encoded as large protein precursors; TGF-β1 contains 390 amino acids and TGF-β2 and TGF-β3 each contain 412 amino acids. They each have an N-terminal signal peptide of 20-30 amino acids that they require for secretion from a cell, a pro-region (called latency associated peptide or LAP), and a 112-114 amino acid C-terminal region that becomes the mature TGF-β molecule following its release from the pro-region by proteolytic cleavage.[3] The mature TGF-β protein dimerizes to produce a 25 KDa active molecule with many conserved structural motifs.[4] TGF-β has nine cysteine residues that are conserved among its family; eight form disulfide bonds within the molecule to create a cysteine knot structure characteristic of the TGF-β superfamily while the ninth cysteine forms a bond with the ninth cysteine of another TGF-β molecule to produce the dimer.[5] Many other conserved residues in TGF-β are thought to form secondary structure through hydrophobic interactions. The region between the fifth and sixth conserved cysteines houses the most divergent area of TGF-β molecules that is exposed at the surface of the molecule and is implicated in receptor binding and specificity of TGF-β. Function The SMAD Pathway The DAXX Pathway Apoptosis TGF-β induces apoptosis in numerous cell types. TGF-β can induce apoptosis in two ways: through the SMAD pathway or the DAXX pathway. SMAD pathway The SMAD pathway is the canonical signaling pathway that TGF-β family members signal through. In this pathway, TGF-β...
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