12 - TGF-β signaling in stem cells and tumorigenesis

Summary

The transformation growth factor-β (TGF-β) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo, including cell growth, cell differentiation, apoptosis, cellular homeostasis, and other cellular functions, and deregulation of the pathway can result in tumor development. TGF-β signaling maintains tissue homeostasis and prevents tumorigenesis by regulating cellular proliferation, differentiation, survival, and micro-environment. Malignant cells can overcome the tumor-suppressive effects of TGF-β, usually through two different mechanisms. First, inactivation of core components of the pathway, demonstrated as frequent mutations of core proteins, results in loss of function in TGF-β signaling in many cancers. Second, downstream alterations that disable just the tumor-suppressor arm of the pathways, allow cancer cells to utilize the remainder of the TGF-β pathway for invasion and metastasis. Insight into the powerful TGF-β pathway in the context of type and stage of cancer, micro-environment, and alteration of other signaling transduction pathways within the cancer cells is crucial to decipher the role of TGF-β as tumor suppressor or promoter, followed by the development of anti-cancer therapeutics targeting TGF-β signaling.

Molecular mechanism of TGF-β signaling: ligands, receptors, and signaling molecules, the Smads

TGF-β represents a large family of pleiotrophic growth and differentiation factors that include activin/inhibins and bone morphogenetic proteins (BMPs) (1–3). These proteins mobilize a complex signaling network to control cell fate by regulating differentiation, proliferation, motility, adhesion, and apoptosis. TGF-β is represented by three isoforms, TGF-β1, -β2, and -β3, TGF-β is secreted as an inactive latent homodimeric polypeptide that is bound to other extra-cellular proteins (4–6). The mature, bioactive ligand is produced upon proteolytic cleavage of the latent complex. Binding of the active TGF-β dimer to the type I and II receptors results in the activation of type II (TβRII), which phosphorylates and activates type I (TβRI), then propagates the signals by phosphorylating Smad transcription factors (Figure 12.1). Smad proteins together comprise a unique signaling pathway with key roles in signal transduction by TGF-β. Currently, at least eight vertebrate Smads have been identified (1,7,8). They are characterized by homologous regions at their N- and C-termini known as Mad homology, MH-1 and MH-2 domains, respectively.