TGF‐β signaling: A tale of two responses

Abstract Transforming growth factor‐β (TGF‐β) regulates a wide variety of cellular processes including cell growth, apoptosis, differentiation, migration, and extracellular matrix production among others. The canonical signaling pathway induced by the TGF‐β receptor complex involves the phosphorylation of Smad proteins which upon activation accumulate in the nucleus and regulate transcription. Interestingly, the cellular response to TGF‐β can be extremely variable depending on the cell type and stimulation context. TGF‐β causes epithelial cells to undergo growth arrest and apoptosis, responses which are critical to suppressing carcinogenesis, whereas it can also induce epithelial‐mesenchymal transition and mediate fibroblast activation, responses implicated in promoting carcinogenesis and fibrotic diseases. However, TGF‐β induces all these responses via the same receptor complex and Smad proteins. To address this apparent paradox, during the last few years a number of additional signaling pathways have been identified which potentially regulate the different cellular responses to TGF‐β. The identification of these signaling pathways has shed light onto the mechanisms whereby Smad and non‐Smad pathways collaborate to induce a particular cellular phenotype. In this article, we review TGF‐β signaling in epithelial cells and fibroblasts with a focus on understanding the mechanisms of TGF‐β versatility. J. Cell. Biochem. 102: 593–608, 2007. © 2007 Wiley‐Liss, Inc.