Biology of Transforming Growth Factor-β Signaling

Transforming growth factor (TGF)-beta 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-beta depends on the cell type and the context in which TGF-beta signaling is received. TGF-beta ligands, their receptors, and intracellular Smad effectors lie in the center of TGF-beta signaling. TGF-beta 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-beta stimulation. In addition, numerous factors constitute complex networks to regulate TGF-beta 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-beta signaling and describe several factors which make up TGF-beta signaling networks. We also address major TGF-beta-induced cell responses involved in several physiological and pathological conditions, including cell proliferation, fibrosis, and epithelial-mesenchymal transition.