Biology of transforming growth factor-β signaling.

Transforming growth factor (TGF)-β signaling has been implicated as an important regulator of almost all major cell behaviors, including proliferation, differentiation, cell death, and motility. Which cell responses are induced or suppressed in response to TGF-β depends on the cell type and the context in which TGF-β signaling is received. TGF-β ligands, their receptors, and intracellular Smad effectors lie in the center of TGF-β signaling. TGF-β ligands signal via receptor serine/threonine kinases that phosphorylate and activate Smad proteins as well as other signaling molecules. Smad complexes associate with chromatin and regulate transcription, defining the biological response of a cell to TGF-β stimulation. In addition, numerous factors constitute complex networks to regulate TGF-β signaling and to provide this cytokine with the ability to induce cellular context-specific cell responses. Perturbation of the network is strongly involved in various pathological situations, including cancer and fibrosis. In this review, we consider the basic machinery of TGF-β signaling and describe several factors which make up TGF-β signaling networks. We also address major TGF-β-induced cell responses involved in several physiological and pathological conditions, including cell proliferation, fibrosis, and epithelial-mesenchymal transition.