Signaling Mechanisms of Transforming Growth Factor-β (TGF-β) in Cancer: TGF-β Induces Apoptosis in Lung Cells by a Smad-Dependent Mechanism

Abstract

1.1 TGF-β ligands, receptors and smads Transforming Growth Factor-beta (TGF-β), a cytokine that is expressed in a variety of normal tissues, including the lung (Bartram & Spear, 2004; Jakowlew et al., 1995, 1998; Kang et al., 2000; Montuenga et al., 1998), exerts diverse effects on a wide variety of cellular processes, including proliferation, differentiation, and apoptosis (Elliot & Blobe, 2005; Massague, 1998). More than sixty different TGF-β family members have been identified in various oraganisms, with at least 29 of these proteins being encoded in humans. Among the many proteins in the TGF-β superfamily are four TGF-β ligands, five activins, eight bone morphogenetic proteins (BMP), and 15 growth and differentiation factors (GDF). Three TGF-β isoforms have been identified in humans, including TGF-β1, TGF-β2, and TGF-β3, with each being a homodimeric polypeptide with a molecular weight of 25-kDa. All three TGF-β isoforms are initially synthesized as 55-kDa proproteins that consist of an amino-terminal pro-region and a carboxy-terminal mature region (Gentry et al., 1988). The pro-region facilitates necessary dimerization of the proproteins for future activity. TGF-β is secreted in a latent, inactive form in which the 12.5kDa carboxyl-terminal 112 amino acid-long mature form is non-covalently associated with the 80-kDa Latency-Associated Peptide (LAP) amino-terminal remainder (Barcellos-Hoff, 1996; Barcellos-Hoff & Ewan, 2000). The LAP forms a complex with the 12.5-kDa TGF-β to keep it inactive (Arndjelovic et al., 2003; Stander et al., 1999). This complex is referred to as the small latent TGF-β complex. The small latent TGF-β complex may associate with members of the latent TGF-β-binding protein (LTBP) family to form the large latent TGF-β complex (Oklu & Hesketh, 2000). The liberation of TGF-β from the latent complexes is referred to as activation (Annes et al., 2003). The precise steps that are involved in liberation of the bioactive dimer are not completely understood, but may involve cleavage of the LTBP or LAP or both (Hyytiainen et al., 2004). Active TGF-β exerts its effects with specific high affinity receptors. In mammals, five TGF-β superfamily type I receptors and seven type II receptors have been identified (Derynck et al.,