TGFβ Signal Transduction

Publisher Summary Transforming Growth Factor β (TGFβ) superfamily members are expressed and function ubiquitously throughout early development and the lifetime of higher animals from worms to humans. TGFβ ligands transduce their signals into cells via transmembrane serine/threonine kinase receptors. In general, the formation of a heteromeric complex of ligand and receptors induces the phosphorylation of the receptor-regulated Smads (R-Smads) within the cytoplasm. This phosphorylation results in R-Smad activation, freeing the R-Smad from the receptors and allowing for the formation of a heteromeric complex with the common Smad, Smad4. These active R-Smad/Smad4 complexes accumulate in the nucleus, and function in conjunction with a host of nuclear co-factors to regulate the transcription of target genes. TGFβ family members transduce signals across the plasma membrane via the formation of an active heteromeric complex of type II and type I receptors. Smads are the best-characterized intracellular mediators of TGFβ signals. They are a group of eight structurally related proteins in humans with homologs identified in organisms as diverse as worms to humans. The MH1 domain is responsible for nuclear import, DNA binding, and interactions with transcription factors, while the MH2 mediates interactions with receptors, Smad oligomerization, and interactions with transcription factors, co-activators, and co-repressors. While the inhibitory Smads (I-Smads), Smad6 and Smad7, share structural similarities with the R-Smads, they function to negatively regulate TGFβ signaling. I-Smads inhibit TGFβ signaling by targeting different points within the signaling cascade.