Holding their own: the noncanonical roles of Smad proteins.

The identification of Smads as protein transcription factors in 1995 led to elucidation of the canonical transforming growth factor-beta (TGF-beta) signaling pathway. In the years that have followed, nuances of the pathway have been realized, and the once-simple scheme of ligand to receptor to activated transcription factor is now understood to be highly regulated at each step and riddled with crosstalk from other pathways. The Smads are also recognized as important players outside of canonical TGF-beta-dependent signaling and are responsible for regulating diverse cellular processes. New evidence suggests that Smad7 plays an integral role in maintaining cell-cell adhesion through direct regulation of beta-catenin. Receptor-activated Smads regulate the processing of a subset of microRNAs, particularly miR-21. The number of reports demonstrating the interactions of Smads with proteins outside of canonical TGF-beta signaling is increasing, although the functional relevance of these interactions is not known. Investigating these interactions will likely yield more evidence that Smads serve important and diverse purposes beyond their original reported function as signal transducers in the TGF-beta pathway.