Navigation Links
Researchers describe new molecular interactions behind the inhibition of TGF beta-signaling
Date:8/24/2012

This press release is available in Spanish.

Researchers headed by Maria Macias an ICREA researcher at the Institute for Research in Biomedicine (IRB Barcelona) and Joan Massagu, a Howard Hughes Medical Institute investigator at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, have identified a new molecular mechanism that plays a crucial role in the control of the activation of certain genes associated with cancer.

Through detailed structural and biochemical studies, the researchers identified a key domain present in a family of proteins called Smads, whose binding determines whether the transcription of genes controlled by the TGF-beta and BMP signaling cascades will be bound by activators or labeled for degradation. These processes are critical to the correct development and maintenance of tissues and organisms.

When looking at inhibitory Smads , the researchers found that the specific domain binds directly and constitutively to their targets. This is in contrast to what happens with receptor-activated Smads, where the proteins must first undergo processing by phosphorylation a chemical change whereby the proteins are first activated and then labeled for degradation after completing their transcriptional function. The study appears online today (August 23) in the journal Structure.

Smads are key proteins in the signaling pathways of the hormones TGF-beta and BMP, which are known to participate in the control of stem cell pluripotency and differentiation and in the development and maintenance of metazoan organisms. In this study, the researchers looked at the interactions of Smad7 a protein inhibitor of TGF-beta signaling with molecules implicated in the cascade, including three ubiquitin ligases and YAP, a transcription coactivator. They identified the domains in the four proteins that interact with the same region of Smad7 and quantified these interactions in terms of affinity values.

Previous work by the groups on a similar type of protein, called receptor-activated Smads, has shown that in order for transcription to take place, these Smads undergo the process of phosphorylation. In this study, which focuses on inhibitory Smads, the researchers found that this step of molecular processing was not necessary and that the four proteins bind constitutively and directly to the targets.

The TGF-beta pathway is tightly regulated. Its regulation includes a feedback process whereby the two sets of Smads play complementary roles in the same signaling cascade, as they can either inhibit or trigger gene transcription, depending on cell type and the physiological needs of the tissue or organism. As with most biological processes, achieving a fine balance between the two is key, since uncontrolled gene transcription is a hallmark of serious diseases such as cancer. This latest discovery helps to shed light on how organisms achieve this balance.

One of the keys to success of this project was the unique combination of perspectives and methodologies that the partners contributed. Macias' team at IRB Barcelona used a mixture of biophysical and molecular biology techniques to decipher the minute structures of subdomains within the proteins at the atomic level. "The problem," she says, "is that we are looking at small sections of the full proteins in vitro, isolated from their cellular environment. Using techniques such as nuclear magnetic resonance, we are able to see the details down to the atoms in the binding sites. But because we zoom in so closely, we can lose sight of what the interactions we characterize can actually mean for the function of the entire protein in the cell."

Massagu's group at MSKCC was able to take each of Macias' detailed conformational changes and, using mammalian cells and full length proteins, see the effects these changes had in the cells. "Merging the detailed and bigger pictures is a difficult but key step to understanding the nature of biological processes, and to identifying what happens in disease," he says. "Detailed information on the structures of molecules involved in fundamental processes, such as that provided by this study, can tell us where to look to take to control when things go wrong."


'/>"/>
Contact: Sarah Sherwood
sarah.sherwood@irbbarcelona.org
34-934-034-636
Institute for Research in Biomedicine (IRB Barcelona)
Source:Eurekalert

Related biology news :

1. U of M researchers: Newly discovered genetic markers could signal colon cancer development
2. Iowa State, Ames Lab researchers study the structure of drug resistance in tuberculosis
3. ORNL researchers improve soil carbon cycling models
4. Researchers identify key culprit causing muscle atrophy
5. Researchers demonstrate control of devastating cassava virus in Africa
6. Researchers pursue red flag for schizophrenia relapse
7. A new line of defense: Researchers find cattle vaccine works to reduce E. coli O157:H7
8. Iowa State, Ames Lab researchers invent new tool to study single biological molecules
9. Wayne State researchers working to improve genetic analysis, disorder detection
10. Superbird stuns researchers
11. Massachusetts Eye and Ear researchers discover elusive gene that causes a form of blindness from birth
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/15/2016)... 2016  A new partnership announced today will ... decisions in a fraction of the time it ... high-value life insurance policies to consumers without requiring ... Force Diagnostics, rapid testing (A1C, Cotinine and HIV) ... pressure, weight, pulse, BMI, and activity data) available ...
(Date:4/14/2016)... April 14, 2016 BioCatch ... Detection, today announced the appointment of Eyal Goldwerger ... role. Goldwerger,s leadership appointment comes at a ... of the deployment of its platform at several of ... technology, which discerns unique cognitive and physiological factors, is ...
(Date:3/31/2016)... BOCA RATON, Florida , March 31, 2016 /PRNewswire/ ... LEGX ) ("LegacyXChange" or the "Company") ... presentation for potential users of its soon to be ... The video ( https://www.youtube.com/channel/UCyTLBzmZogV1y2D6bDkBX5g ) will also ... by the use of DNA technology to an industry ...
Breaking Biology News(10 mins):
(Date:6/27/2016)...  Global demand for enzymes is forecast to ... $7.2 billion.  This market includes enzymes used in ... production, animal feed, and other markets) and specialty ... and beverages will remain the largest market for ... products containing enzymes in developing regions.  These and ...
(Date:6/27/2016)... ... 2016 , ... Parallel 6 , the leading software as a service ... Virtual Patient Encounter CONSULT module which enables both audio and video telemedicine communication ... , Using the CONSULT module, patients and physicians can schedule a face to face ...
(Date:6/27/2016)... BOSTON , June 27, 2016   Ginkgo ... biology to industrial engineering, was today awarded as ... a selection of the world,s most innovative companies. ... at scale for the real world in the ... organism engineers work directly with customers including Fortune ...
(Date:6/24/2016)... ... 2016 , ... Researchers at the Universita Politecnica delle Marche in Ancona combed ... pleural mesothelioma. Their findings are the subject of a new article on the Surviving ... signposts in the blood, lung fluid or tissue of mesothelioma patients that can help ...
Breaking Biology Technology: