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Smad4 is one of a suite of Smad proteins that facilitate cell-to-cell communication in all animals. Mutations of these proteins have been linked to numerous diseases, including cancer. Now, Arizona State University scientists Stuart Newfeld and Michael Stinchfield, with collaborators from the University of Padova in Italy, have discovered that Smad4 – thought to be a minor player in the regulation of cellular processes (compared to Smad1, Smad2 and Smad3) – is not minor at all. Their findings were featured on the Jan. 9 cover of the journal Cell.
Over the years, oncologists have found that specific types of cancer, such as those in the pancreas and colon, are frequently associated with abnormalities in Smad4, but not with the other Smads. The small role traditionally assigned to Smad4 led the researchers to wonder how it could be so important in cancer, according to Newfeld, an associate professor in ASU’s School of Life Sciences in the College of Liberal Arts and Sciences.
With funding from Science Foundation Arizona and Stinchfield's experiments utilizing the fruit fly Drosophila melanogaster, Newfeld and his colleagues solved this mystery when they discovered a previously unknown mechanism by which cells regulate Smad4.
Newfeld explains that Smad4 was seen as a minor player, a “slave” whose actions were directed by its “masters” – Smads 1, 2 and 3. “So how could Smad4 abnormalities lead to cancer without the co-incidence of problems with the other Smads? This paradox about Smad4’s involvement in cancer couldn’t be easily explained,” he says. “Our research revealed that Smad4 was a slave with a secret."
It is well known that a complex organism arises from a single cell, a fertilized egg. According to Newfeld, this process is only possible through constant “cross-talk” between cells as they begin dividing and multiplying. Each cell in an organism contains the entire set of instructions necessary to make that organism, but individual cells only need to utilize subsets of these instructions. Cells have to communicate with each other in order to know which instructions to use, telling them where and how to grow, what types of cells to become, and when to stop growing, he says.
Smad proteins are part of a larger cellular communication system studied in Newfeld’s lab called the transforming growth factor-beta (TGF-beta) system. The system is activated when receptors embedded in the outer membrane of a cell detect TGF-beta proteins secreted by other cells. These receptors, in turn, Newfeld explains, “activates Smad 1 or 2 or 3 (the masters) which then join with Smad4 (the slave).” Once these two pair up, they go into the nucleus of the cell and turn on genes that encode proteins necessary for implementing the TGF-beta instructions. The prevailing wisdom was that without another Smad as a partner, Smad4 does nothing.
What Newfeld and the other researchers discovered, however, is that Smad4 can be tagged with another small protein, called ubiquitin, in a process that has nothing to do with the other Smads.
“If Smad4 gets tagged with one ubiquitin it is temporarily deactivated, but if it gets tagged with four it is destroyed,” he relates. A Smad4 molecule that has been deactivated or destroyed can’t team up with another Smad. When a large number of Smad4 molecules are ubiquitin-tagged, this can mean that the normal information transfer between cells is dampened, sending the cell down the wrong path and resulting in a developmental defect or a tumor.
Newfeld says that one major impact of this new understanding of Smad4 and the discovery of the importance of ubiquitin in Smad4 activity is the possibility that the ubiquitin-manipulating proteins of the cell are now potential targets for anti-cancer drug screening.
“Cancer screening is expensive, but, by focusing on plausible targets identified by independent evidence, the process becomes much more efficient,” Newfeld says. The anti-cancer potential of the discovery by Newfeld and his colleagues is being explored in collaboration with the Clinical Translational Research Division at the Translational Genomics Research Institute (TGen) in Phoenix, Ariz.
Rick Overson, firstname.lastname@example.org
College of Liberal Arts & Sciences