Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers discover new insight into a common signaling pathway

01.08.2002


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.

Heather Cosel | EurekAlert!

More articles from Life Sciences:

nachricht More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>