The signal transduction mechanisms underlying the pathophysiological activities of transforming growth factor-β (TGF-β) have been extensively studied since its discovery nearly 30 years ago. TGF-β ligands belong to a large superfamily of cytokines that bears its name (TGF-β Superfamily) and includes bone morphogenic proteins (1), activins (2), inhibin (3), growth/differentiation factors (4), Mullerian inhibiting substance (5), Nodal (6), and several other structurally-related polypeptides (7). Mammals express three TGF-β isoforms (i.e., TGF-β1, TGF-β2, and TGF-β3) that are encoded by distinct genes in a tissue-specific and developmentally-regulated manner (8). TGF-β was identified originally via its stimulation of morphological transformation and anchorage-independent growth in fibroblasts; however, this cytokine is now recognized as being a potent tumor suppressor that prevents the dysregulated growth and survival of epithelial, endothelial, and hematopoietic cells (8,9,10,11). In addition, numerous studies have clearly established TGF-β as a multifunctional cytokine that plays essential roles in regulating virtually all aspects of mammalian development and differentiation, and in maintaining mammalian tissue homeostasis (8,9,10,11). The pleiotropic nature of TGF-β is highlighted by the fact that every cell in the metazoan body can produce and respond to this cytokine. Even more remarkably, malignant cells have evolved a variety of complex mechanisms capable of circumventing the tumor suppressing activities of TGF-β, and in doing so, typically convert the functions of TGF-β to that of a tumor promoter, particularly the induction of carcinoma epithelial-mesenchymal transition, invasion, and dissemination to distant organ sites (8,9,10,11). This peculiar conversion in TGF-β function is known as the “ TGF-β Paradox,” which underlies the lethality of TGF-β in metastatic cancer cells. Thus, elucidating the effectors and signaling modules activated by TGF-β may offer new insights into the development of novel neoadjuvants capable of effectively targeting the TGF-β pathway to significantly improve the clinical course of patients with cancer, fibrosis, or immunologic disorders.
TGF-β is secreted from cells as a latent homodimeric polypeptide that becomes tethered to the extracellular matrix by latent-TGF-β-binding proteins. Mature TGF-β isoforms are activated and liberated from extracellular matrix depots by a variety of mechanisms, including proteolysis, reactive oxygen species, changes in pH, and physical interactions with integrins, thromobspondin-1, or SPARC (12,13,14,15). Once activated, mature TGF-β initiates transmembrane signaling by binding to two distinct transmembrane Ser/Thr protein kinases, termed TGF-β type I (TβR-I) and type II (TβR-II) receptors (16,17,18). In some cells and tissues, TGF-β also binds to a third cell surface receptor, TGF-β type III (TβR-III), which transfers TGF-β to TβR-II and TβR-I (19). Full activation of these cytokine:receptor ternary complexes transpires upon TβR-II-mediated transphosphorylation and activation of TβR-I (20,21), which then phosphorylates and activates the latent transcription factors, Smad2 and Smad3 (22,23). Afterward, phosphorylated Smad2/3 interact physically with Smad4, with the resulting heterotrimers translocating into the nucleus to regulate the expression of TGF-β-responsive genes (22,23). As depicted in Figure 1, these Smad-dependent events are subject to fine-tuning and crosstalk regulation in the cytoplasm by their interaction with a variety of adapter molecules, including SARA, Hgs, PML and Dab2 (24,25,26,27), and with Smad7 (28,29), whose inhibitory activity is modulated by STRAP, AMSH2, and Arkadia (30,31,32); and in the nucleus by their interaction with a variety of transcriptional activators and repressors that occur in a gene- and cell-specific manner (33). In addition to activating canonical Smad2/3-dependent signaling, accumulating evidence clearly links the development of a variety of human pathologies to aberrant coupling of TGF-β to its noncanonical effector molecules. Included in this ever expanding list of noncanonical signaling molecules stimulated by TGF-β are PI3K (34), AKT (35), mTOR (36), integrins (37) and focal adhesion kinase (38), and members of the MAP kinase (e.g., ERK1/2 (39), JNK (40), and p38 MAPK (41) small GTP-binding proteins (e.g., Ras, Rho, and Rac1) (11). The interactions and intersections between canonical and noncanonical TGF-β signaling systems are depicted in the pathway map.
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