The Mechanism of Tgf-β Signaling

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates proliferation, differentiation, development, angiogenesis, wound healing and other functions in many cell types (Massagué, 2008). Regarding pathological disorders, such as cancer, TGF-β plays two confl icting roles of a tumor suppressor and a tumor promoter. TGF-β acts as a tumor suppressor in the early stage of cancer development, whereas in late stage it can take on role of tumor promoter, favoring of invasion and metastasis (Mishra et al., 2005; Padua and Massagué, 2009). TGF-β is a one of members of a large superfamily of secreted proteins that include three TGF-β isoforms (TGF-β1, -β2 and -β3), activins, bone morphogenetic proteins (BMPs), inhibins, nodal, and others. Cancer cells, in general, secrete larger amounts of TGF-β than their normal counterparts (Kingsley, 1994; Massagué, 2000). TGF-β is secreted from the cell as an inactive latent homodimeric polypeptide bound to other extracellular proteins (Roberts and Wakefi eld, 2003; Muraoka-Cook et al., 2005). The mature, bioactive TGF-β is produced on proteolytic cleavage of the latent complex. TGF-β interacts with its four receptor subunits that interact not only with TGF-β, but also with each other. Understanding the detailed mechanism of the interactions between TGF-β and its receptors presents potential opportunities to fi nd new drugs. Such drugs or blockades could be designed to inhibit the assembly of the TGF-β signaling complex and in turn eliminate its tumor-promoting activities.