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

exerts diverse effects on a wide variety of cellular processes, including proliferation, differentiation, and apoptosis (Elliot & Blobe, 2005; More than sixty different TGF- 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- superfamily are four TGF- ligands, five activins, eight bone morphogenetic proteins (BMP), and 15 growth and differentiation factors (GDF). Three TGF- isoforms have been identified in humans, including TGF-1, TGF-2, and TGF-3, with each being a homodimeric polypeptide with a molecular weight of 25-kDa. All three TGF- isoforms are initially synthesized as 55-kDa proproteins that consist of an amino-terminal pro-region and a carboxy-terminal mature region The pro-region facilitates necessary dimerization of the proproteins for future activity. TGF- is secreted in a latent, inactive form in which the 12.5-kDa carboxyl-terminal 112 amino acid-long mature form is non-covalently associated with the 80-kDa Latency-Associated Peptide (LAP) amino-terminal remainder The LAP forms a complex with the 12.5-kDa TGF- to keep it inactive (Arndjelovic et al., 2003; This complex is referred to as the small latent TGF- complex. The small latent TGF- complex may associate with members of the latent TGF--binding protein (LTBP) family to form the large latent TGF- complex The liberation of TGF- from the latent complexes is referred to as activation 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 Active TGF- exerts its effects with specific high affinity receptors. In mammals, five TGF- superfamily type I receptors and seven type II receptors have been identified (Derynck et al., www.intechopen.com Tumor Suppressor Genes 146 2001; The TGF- type I and type II receptors are structurally related transmembrane glycoproteins that consist of an extracellular N-terminal ligand-binding domain with more than ten cysteine residues that regulate the dimeric structure, a transmembrane region, and a C-terminal serine/threonine kinase domain. The type I receptors, but not type II receptors, have a highly conserved region that is rich in glycine and serine residues, referred to as the GS domain, in the juxtamembrane domain next to the N-terminus of the kinase domain. The GS domain is a target for the type II receptor kinase, and upon its phosphorylation on specific serine and threonine residues, the type I receptor becomes activated Being downstream of the type II receptor, the type I receptor plays an important role in determining the specifity of intracellular signals. The type I and II receptors exist as homodimers at the cell surface in the absence of ligands, but have an inherent heteromeric affinity for each other. Only select combinations of type I and II receptors act as ligand-binding signaling complexes. The molecular basis of the selectivity of the type I-type II receptor interactions remains poorly understood, but the structural complement at the interface may help define the selectivity of the receptor combinations. Most of the TGF- ligands bind with high affinity to the type I receptor, also known as activin receptor-like kinase (ALK), or to the type II receptor, while others bind efficiently only to heteromeric receptor combinations. The intracellular signal transduction triggered by the kinase activity of TGF- involves the phosphorylation of Smad family proteins and in turn, complex changes in the transcriptional regulation of various response genes. The Smad family proteins include Smad 1, 2, 3, 4, 5, 7, and 8. The Smads are divided into three subclasses depending on their structure and function: the receptor-regulated Smads (R-Smads), common-mediator Smad (Co-Smad), and inhibitory Smads (I-Smads). In general, the R-Smads, Smads 2 and 3, function downstream of the TGF- ligands, while Smads 1, 5, and 8 are downstream of members of the BMP and GDF subfamilies of ligands. Smads 1, 2, 3, 5, and 8 are direct substrates for the TGF- type I receptor kinase, whereas Co-Smad, Smad 4, participates in Smad complex formation. Smads 6 and 7, the I-Smads, interfere with TGF--induced Smaddependent signal transduction Activation of cell surface receptors by ligands leads to phosphorylation of the R-Smads at two serine residues in a SSXS motif at their extreme C-termini. This phosphorylation allows the R-Smads to form both homomeric and heteromeric complexes with Smad4 that accumulate in the nucleus. There, they are directly involved in transcriptional regulation of target genes in cooperation with other transcription factors. Signaling by TGF- is mediated by a ligand-induced heteromeric complex of two types of transmembrane serine/threonine kinase receptors designated as TGF- type I receptor (TGF- RI) and type II receptor (TGF- RII). Initial ligand binding to constitutively active TGF- RII is followed by recruitment of TGF- RI into the heteromeric complex. Subsequent phosphorylation of TGF- RI at its GS-domain and activation is mediated by TGF- RII and leads to activation of TGF- RI. Upon this activating phosphorylation, TGF- RI phosphorylates the receptor-activated Smad proteins (R-Smads), Smad2 and Smad3, which form a heteromeric complex with the co-Smad, Smad4, and enter the nucleus. In the nucleus, the Smad complex associates with other transcription factors for transcriptional activation of specific target genes (