(Toronto – May 21, 2010) A team of scientists at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, as well as colleagues in Scotland and the United States, have generated a comprehensive road map of the signalling proteins that control many aspects of cellular behaviour in yeast cells.
A greater understanding of these yeast signalling proteins will help researchers better understand similar systems in human illnesses including cancer, and assist in the development of new therapies. The findings were reported in the May 21 issue of the prestigious international journal Science.
By using the Lunenfeld’s leading-edge mass spectrometry laboratory, researchers Drs. Anne-Claude Gingras, Tony Pawson and Mike Tyers studied the interactions of two key classes of enzymes known as protein kinases and phosphatases, referred to as the ‘kinome,’ in cells of the common baker’s yeast, Saccharomyces cerevisiae. The authors analyzed the entire collection of kinases and phosphatases in yeast, and uncovered a dense network of thousands of protein interactions, including many previously uncharacterized proteins. Their findings represent the largest study of this type to date.
“This is the first time that a kinome has been mapped to this extent,” said Lead Author Dr. Tyers. “Our findings suggest that cells are able to integrate many different signals through the global network, and this has implications for how we might design drugs to control networks in health and disease.”
Cells coordinate many of their activities through the actions of protein kinases and phosphatases. To date, only a fraction of the 500 protein kinases in the human genome have been explored. When these proteins malfunction, as occurs in genetic mutation or viral infection, cellular function is perturbed. Blocking a protein kinase or phosphatase implicated in cancer, for example, is the basis for some anti-cancer therapies: some of the newest and most selective, or ‘intelligent,’ therapies are based on the specific inhibition of kinases that are mutated in cancer.
In their study, Drs. Tyers and Gingras studied a specific kinase pathway called ‘TOR’ that controls protein synthesis, and hence helps regulate cell growth. Drugs that inhibit the TOR pathway, including rapamycin, can be used as powerful anti-cancer agents.
“Knowledge of these TOR targets will not only lead to better understanding of the pathway, but may also enable the design of more specific drugs that target the TOR pathway,” said Dr. Tyers.
In the course of their research, the Lunenfeld team also created an innovative computer tool called ProHits, for storing and analyzing the reams of mass spectrometry data, as well as a novel statistical method called SAINT for the analysis of protein interaction data. These freely available research tools—accessible at www.yeastkinome.org
—will allow researchers globally to conduct genome-wide studies of protein interactions and communication pathways in cells.
“The sheer complexity of our data forced us to build statistical tools that we believe will become standard practice for future mass spectrometry-based studies,” said Dr. Gingras.
“These databases and analyses platforms for protein interactions help make the entire scientific literature accessible to all researchers, for the generation of new ideas and hypotheses about how cells function in health and disease,” said Dr. Tyers.
This study was supported by the Canadian Institutes for Health Research, the National Institutes of Health, the Ontario Research Fund, as well as other agencies.