Negative Regulation of the TGF-β Family Signal Pathway by Inhibitory Smads and Their Involvement in Cancer and Fibrosis

Abstract

Transforming growth factor-β (TGF-β) is a pivotal cytokine that regulates cell growth and differentiation of many different cell types (1). TGF-β family signaling initiated by a specific receptor-ligand complex is mainly transmitted to the nucleus via intracellular signal transducing molecules, termed Smads. TGF-β family members, which include TGF-βs, activins, and bone morphogenetic proteins (BMPs), play roles in embryogenesis and maintenance of tissue homeostasis during adult life. In addition, TGF-β family signaling regulates physiological and pathological processes such as wound healing, immunomodulation, apoptosis, and fibrosis. Therefore, the deregulation of TGF-β family signaling is implicated in oncogenesis and heritable disorders (2–4), and the Smad-mediated signaling by the TGF-β family must be tightly regulated. Inhibitory Smads (I-Smads) negatively act for regulation of duration and intensity of TGF-β family signaling. Whereas Smad7 acts as a general inhibitor for the TGF-β family signal pathway. Smad6 preferentially blocks BMP signaling. It has been reported that there are various mechanisms by which I-Smads inhibit the TGF-β family signal pathway (i.e., interaction with type I receptors, R-Smads or transcriptional factors). It has also been reported that several tumors express high levels of I-Smads, leading to blockage of TGF-β family signaling. However, the relevance between tumor development and elevated expression of I-Smads is not clear. In contrast, the expression (or function) of Smad7 is suppressed and augemented in scleroderma and gut inflammation, respectively. On the other hand, there are some reports that I-Smads cooperate with the TGF-β family signal pathway. In this chapter, we focus on recent new insights into the functions of I-Smads (Smad6 and Smad7) and review how I-Smads regulate the TGF-β family signal pathway and are implicated in diseases.