Navigation Links
Researchers describe new molecular interactions behind the inhibition of TGF beta-signaling

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
Institute for Research in Biomedicine (IRB Barcelona)

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:
(Date:10/29/2015)... , Oct. 29, 2015 Daon, a global ... it has released a new version of its ... North America have already installed ... also includes a FIDO UAF certified server component ... preparing to activate FIDO features. These customers include some ...
(Date:10/29/2015)... BOSTON , Oct. 29, 2015  Connected health ... phenomena driving the explosion of technology-enabled health and wellness, ... his new book, The Internet of Healthy ... apps, sensors or smartphones even existed, Dr. Kvedar, vice ... model of health care delivery, moving care from the ...
(Date:10/29/2015)... 29, 2015 Today, LifeBEAM , ... with 2XU, a global leader in technical performance ... hat with advanced bio-sensing technology. The hat will ... monitor key biometrics to improve overall training performance. ... two companies will bring together the most advanced technology, ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... 2015 --> ... "Oligonucleotide Synthesis Market by Product & Services (Primer, Probe, ... DNA, RNAi), End-User (Research, Pharmaceutical & Biotech, Diagnostic Labs) ... market is expected to reach USD 1,918.6 Million by ... CAGR of 10.1% during the forecast period. ...
(Date:11/24/2015)... ... ... The Academy of Model Aeronautics (AMA), led by its Executive Council, has officially ... to represent the First–Person View (FPV) racing community. , FPV racing has exploded in ... racing and several new model aviation pilots have joined the community because of their ...
(Date:11/24/2015)... , November 24, 2015 ... market research report released by Transparency Market Research, the ... at a CAGR of 17.5% during the period between ... Market - Global Industry Analysis, Size, Volume, Share, Growth, ... non-invasive prenatal testing market to reach a valuation of ...
(Date:11/24/2015)... , Nov. 24, 2015 /PRNewswire/ - Aeterna Zentaris ... today that the remaining 11,000 post-share consolidation (or ... Warrants (the "Series B Warrants") subject to the ... on November 23, 2015, which will result in ... giving effect to the issuance of such shares, ...
Breaking Biology Technology: