3 TGF-β: A Multipotential Cytokine

Transforming growth factor-β (TGF-β) has been implicated as an important regulator of almost all major cell behaviors and activities, including proliferation, adhesion, motility, apoptosis, and differentiation. Which of these are affected and how they are regulated in response to TGF-β depend entirely on the cell type and the context in which the TGF-β signals are received. With such a large and diverse set of biological effects in such a wide range of cell types, it is not surprising that layers of regulation and cross-talk impinge on the TGF-β signaling pathway. This chapter provides a basic introduction to the molecular and biological responses controlled by TGF-β and how different levels of input help to regulate the specificity of these responses. Subsequent chapters discuss in greater depth the signaling mechanisms and different aspects of the cellular responses to TGF-β and TGF-β family proteins. TGF-β SIGNALS MEDIATE CHANGES IN GENE EXPRESSION To elicit gene expression responses, TGF-β uses a well-characterized signal transduction pathway that extends from the cell membrane to the nucleus (see Chapter 6). This signaling cascade is initiated when active TGF-β ligand binds to the TGF-β type II receptor (TβRII), which then forms a complex with the TGF-β type I receptor, known as TβRI or activin receptor–like kinase-5 (ALK-5). Formation of this activated ligand-bound receptor complex results in the phosphorylation of TβRI/ALK-5 by TβRII, thereby activating the type I receptor and permitting binding of Smad2 and/or Smad3. These receptor-activated Smads (R-Smads) are subsequently directly phosphorylated by TβRI/ALK-5 at the carboxyl...