TGF-β signal transduction spreading to a wider field: a broad variety of mechanisms for context-dependent effects of TGF-β.

Transforming growth factor (TGF)-β signaling is involved in almost all major cell behaviors under physiological and pathological conditions, and its regulatory system has therefore been vigorously investigated. The fundamental elements in TGF-β signaling are TGF-β ligands, their receptors, and intracellular Smad effectors. The TGF-β ligand induces the receptors directly to phosphorylate and activate Smad proteins, which then form transcriptional complexes to control target genes. One of the classical questions in the field of research on TGF-β signaling is how this cytokine induces multiple cell responses depending on cell type and cellular context. Possible answers to this question include cross-interaction with other signaling pathways, different repertoires of Smad-binding transcription factors, and genetic alterations, especially in cancer cells. In addition to these genetic paradigms, recent work has extended TGF-β research into new fields, including epigenetic regulation and non-coding RNAs. In this review, we first describe the basic machinery of TGF-β signaling and discuss several factors that comprise TGF-β signaling networks. We then address mechanisms by which TGF-β induces several responses in a cell-context-dependent fashion. In addition to classical frames, the interaction of TGF-β signaling with epigenetics and microRNA is discussed.