Receptor-activated transcription factors and beyond: multiple modes of Smad2/3-dependent transmission of TGF-β signaling.

Transforming growth factor β (TGF-β) is a pleiotropic cytokine that is widely distributed throughout the body. Its receptor proteins, TGF-β type I and type II receptors, are also ubiquitously expressed. Therefore, the regulation of various signaling outputs in a context-dependent manner is a critical issue in this field. Smad proteins were originally identified as signal-activated transcription factors similar to signal transducer and activator of transcription proteins. Smads are activated by serine phosphorylation mediated by intrinsic receptor dual specificity kinases of the TGF-β family, indicating that Smads are receptor-restricted effector molecules downstream of ligands of the TGF-β family. Smad proteins have other functions in addition to transcriptional regulation, including post-transcriptional regulation of micro-RNA processing, pre-mRNA splicing, and m6A methylation. Recent technical advances have identified a novel landscape of Smad-dependent signal transduction, including regulation of mitochondrial function without involving regulation of gene expression. Therefore, Smad proteins are receptor-activated transcription factors and also act as intracellular signaling modulators with multiple modes of function. In this review, we discuss the role of Smad proteins as receptor-activated transcription factors and beyond. We also describe the functional differences between Smad2 and Smad3, two receptor-activated Smad proteins downstream of TGF-β, activin, myostatin, growth and differentiation factor (GDF) 11, and Nodal.