Researchers discover new insight into a common signaling pathway

Scientists have identified a key regulatory mechanism in the TGF-ß pathway. This discovery by Dr. Kai Lin and colleagues at UMASS Medical School and the University of Mississippi Medical Center helps further our understanding of how this important signaling pathway functions in a variety of cellular processes, including cancer formation and embryonic development.

The work is published in the August 1 issue of Genes & Development.

The TGF-ß pathway is an intracellular signaling pathway that enables a cell to respond to changes in its environment. This signal transduction pathway converts ligand binding at the cell surface into an enzymatic cascade inside the cell, which ultimately induces changes in gene expression. In this fashion, the TGF-ß pathway regulates a number of different cellular responses, including cell proliferation, differentiation and migration, programmed cell death, and development.

The Smad family of proteins is the primary route for propagating the TGF-ß signal. Smads are activated by ligand-bound transmembrane receptors and subsequently travel through the cytoplasm and into the nucleus, where they act as transcription factors to activate the expression of TGF-ß target genes.

Dr. Lin and colleagues have determined that the conformation of the Smad3 protein specifies which members of the TGF-ß pathway it can interact with, and thereby regulates the progression of the TFG-ß signal transduction cascade.

Upon TGF-ß ligand binding to transmembrane receptors at the cell surface, a protein called SARA (Smad Anchor for Receptor Activation) recruits Smad3 to the transmembrane receptor, where Smad3 is converted from an inactive monomeric form into an active trimeric form. Trimeric Smad3 promptly dissociates from SARA and enters the nucleus, where it interacts with cofactors to regulate gene expression. Previous work has shown that nuclear Smad3 interacts with a corepressor called “Ski,” which serves to prevent Smad3 activation of target genes.

Using a combination of structural and biochemical approaches, Dr. Lin and colleagues discovered that SARA preferentially binds to monomeric Smad3, while Ski preferentially binds to trimeric Smad3. The researchers thus identified an allosteric mechanism of regulation of the TGF-ß pathway: “The conformational transition functions as a master switch of the pathway, converting Smad-receptor interactions to Smad-nuclear interactions,” explains Dr. Lin. The formation of trimeric Smad3 transduces the TGF-ß signal by forcing Smad3 to dissociate from SARA, thereby freeing Smad3 to travel into the nucleus.

In this manner, the conformation-dependent activity of Smad3 can both propagate the TGF-ß signal and establish a negative feedback mechanism (through Ski) to regulate the transcriptional effect of TGF-ß signaling.

So, how does a cell succeed in eliciting TGF-ß target gene expression if trimeric Smad3 is bound in the nucleus by Ski, a corepressor? The authors reason that the trimeric form of Smad3 is probably also recognized by coactivators in the nucleus, which would compete with Ski for Smad3 binding and ultimately establish the appropriate balance between transcriptional activation and repression. Further research will focus on delineating the course of these downstream nuclear events.

However, as it stand now, this work by Dr. Lin and colleagues affords enormous insight into the molecular mechanisms of the TGF-ß signaling pathway, providing possible targets for rational drug design to combat the deleterious effects of aberrant TGF-ß signaling.