| Transforming growth factor-β (TGF-β) superfamily members are critical regulators of cell proliferation and differentiation, developmental patterning and morphogenesis, and disease pathogenesis (1-4). TGF-β elicits signaling through three cell surface receptors: type I (RI), type II (RII), and type III (RIII). Type I and type II receptors are serine/threonine kinases that form a heteromeric complex. In response to ligand binding, the type II receptors form a stable complex with the type I receptors allowing phosphorylation and activation of type I receptor kinases (5). 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 (6,7). Expression of the type III receptor can regulate TGF-β signaling through presentation of the ligand to the signaling complex. The only known direct TGF-β signaling effectors are the Smad family proteins, which transduce signals from the cell surface directly to the nucleus to regulate target gene transcription (8,9).There are three isoforms of TGF-beta designated TGF-beta1, TGF-beta2, and TGF-beta3, which are encoded by distinct genes and are expressed in a tissue specific manner (10). Each of the isoforms are synthesized as larger precursor proteins containing a propeptide region which gets cleaved prior to secretion from the cell. Mature TGF-beta contains two polypeptides linked linked by disulfide bonds forming a protein of about 25 kDa. |
