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Signaling Star As one of the 25 most highly cited scientists for a decade, Tony Pawson has proposed ideas in cell signaling that are now shaping treatment strategies for some of the world’s most important diseases. By Kelly Rae Chi © 2010 Icon Photography Inc./www.iconphotoinc.
January 14, 2010|
In the early 1980s, Tony Pawson made a discovery that would eventually shape scientists’ views of the proteins involved in cell signaling and lead to promising new strategies for treating cancer and other diseases. It just took a little while.
At the time, he was an assistant professor at the University of British Columbia in Vancouver, trying to figure out how healthy cells turned cancerous through disruptions in their signaling mechanisms. In one example of this type of disruption, a landmark paper published in 1970 in Nature, scientists showed that the overexpression of a single gene called Src in the Rous sarcoma virus caused cancer in tissue infected with the virus. Later studies showed that Src’s protein was a tyrosine kinase, a major player in cell signaling that works by adding phosphate groups to a protein’s tyrosines. Working on a similar cancer-causing gene called Fps, a tyrosine kinase in the Fujinami sarcoma virus, with Michael Smith—the pioneer of site-directed mutagenesis, for which he won a 1993 Nobel Prize in Chemistry—Pawson’s group mutated different spots on Fps to try to figure out which parts of the protein triggered cell proliferation. There was one piece, called the kinase domain, that they knew was critical, but mutagenesis revealed that the sequence preceding it was also important.
Pawson soon realized that the sequence preceding the kinase domain on Fps was present in several other cancer-causing proteins, including Src. In both Fps and Src, the protein fragment was critical to guiding the entire protein to its intended target, a key step in converting cells to a cancerous state. Not knowing how important the fragment was, Pawson named it Src homology 2 domain, or SH2, and described it in a paper published in Molecular and Cellular Biology in 1986. As he began to see how critical fragments like SH2 were, it led him to propose that signaling proteins have different domains with different functions.
The notion that proteins are modular—composed of parts with distinct functions—was completely new. It initially met resistance among cell biologists, especially those who studied kinases. At the time, it was thought that messages were transmitted within cells primarily through enzymatic reactions such as phosphorylation, whose effect was to change the conformation and thus the activity of the substrate. The idea that there were certain protein domains such as SH2 that, just by making physical contact with the right protein, were sufficient to transmit a signal within the cell was “somewhat heretical” at that time, recalls Pawson, who is now an investigator at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital and a professor at the University of Toronto.
“I thought we either were completely up the creek and had things wrong or it was a really important and new idea,” Pawson recalls. In the following years, the thinking of his colleagues shifted as Pawson and other researchers went on to discover SH2 domains in at least one hundred other proteins involved in cell proliferation and metabolism. In 1989, his group isolated SH2 domains and showed that they bound selectively to specific activated receptors, demonstrating that the receptor-SH2 interaction could change cell behavior. In the 5 years following his original study in Molecular and Cellular Biology, the hypothesis gained traction. The paper has been cited nearly 400 times.
“Now that view is pretty much entrenched. That’s the way we understand proteins,” says cancer researcher Piers Nash from the University of Chicago, and a former postdoc of Pawson’s. The findings allowed Nash and other researchers to pick out individual proteins’ parts and study them in depth in solution. “That combination of a reductionist approach with actually being able to look at proteins in the biology of cells is really very powerful and really continues to be,” Nash adds.
Over the years, Pawson has won numerous awards and honors, including the 2008 Kyoto Prize in Basic Science, for proposing and showing that protein–protein interactions form basic elements of cell signaling. For a decade, he has been one of the top 25 most highly cited scientists. “I’d say that the secret to his success is that he thinks about important questions and has original ideas about how to solve problems,” says cell biologist Steven Martin at the University of California, Berkeley, who discovered Src and mentored Pawson when he was a postdoc.
Pawson’s ideas are beginning to open a unique approach to drug development. Historically, it had been thought that protein–protein interactions like the ones Pawson’s group revealed would be too difficult to inhibit using small molecules. “That has now changed and there are examples of very exciting drugs in the clinic,” Pawson says. For instance, Novartis’s cancer drug Gleevec works by targeting and turning off tyrosine kinases that cause cells to grow and multiply. First approved by the US Food and Drug Administration in 2001, the drug is used to treat chronic myeloid leukemia, gastrointestinal stromal tumor, and other cancers. ABT-263, a drug made by Abbott Laboratories that induces apoptosis through protein– protein interactions, is being tested in Phase I clinical trials.
Pawson’s early discoveries blossomed into a field, and his group is now working on several areas, one of them focusing on signaling of ephrin tyrosine kinase receptors and ephrins, proteins that are important in guiding neuron fibers to their proper targets and are implicated in some forms of cancer. Pawson’s team has moved into bidirectional cell signaling—crosstalk between two different cell types—to understand how these signals help cells group together in the proper tissues. In 2009, he and his group reported in Science that signaling between mixed ephrin-B2– and ephrin-B1–expressing cells, which are present in the developing brain, is asymmetrical and that each cell type uses a different type of tyrosine kinase to process those signals. The researchers are using these findings and others to build computer-based models of cell signaling that give an idea of how truly complex protein–protein interactions are, which could shed light on how they might go awry in brain diseases and cancer.
It’s now also becoming clear that a protein’s function is determined by the type, arrangement, and number of domains it includes. Even a single domain can change through genetic rearrangements and mutations. Using bioinformatics and proteomics, Pawson’s group is interested in how those combinations have evolved. For a 2009 study in Science Signaling, his group examined the proteomes of seven different eukaryotes—including yeast, fish, chickens, and humans—to see how domains change from one species to another. Some domains are conserved across species; others decay.
Pawson has 20 people in his lab, and he is continuing to make large leaps in the world of signal transduction. “He hasn’t been one to rest on his laurels,” Nash says. “He’s continually reinventing the field.”