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 Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg

nachricht Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Electrode materials from the microwave oven

19.10.2017 | Materials Sciences

New material for digital memories of the future

19.10.2017 | Materials Sciences

Physics boosts artificial intelligence methods

19.10.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>