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Researchers discover new insight into a common signaling pathway

Scientists have identified a key regulatory mechanism in the TGF- 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- 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- 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- 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- target genes.

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

Upon TGF- 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 act
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Contact: Heather Cosel
coselpie@cshl.org
Cold Spring Harbor Laboratory
31-Jul-2002


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