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Transforming growth factor-beta (TGF-beta) superfamily signaling plays a critical role in the regulation cell growth, differentiation, and development in a wide range of biological systems. Signaling is initiated with ligand-induced oligomerization of serine/threonine receptor kinases and phosphorylation of the cytoplasmic signaling molecules Smad2 and Smad3 for the TGF-beta/activin pathway, or Smad1/5/8 for the bone morphogenetic pathway, or BMP. C-terminal phosphorylation of Smads by activated receptors results in their partnering with the common signaling transducer Smad4 and translocation to the nucleus. Activated Smads regulate diverse biological effects by partnering with transcription factors resulting in cell-state specific modulation of transcription. The activin and BMP pathways are themselves attenuated by MAPK signaling at a number of levels, while the expression of inhibitory, or I-Smads 6 and 7 is induced by both activin/TGF-beta and BMP signaling as part of a negative feed-back route.
