[Editors] Model aids understanding of protein networks

[Elizabeth Thomson]

MIT News Office
Massachusetts Institute of Technology
Room 11-400
77 Massachusetts Avenue
Cambridge, MA  02139-4307
Phone: 617-253-2700
http://web.mit.edu/newsoffice/www

======================================
Team's model aids understanding of protein networks
--Work could impact cancer research

======================================

For Immediate Release
TUESDAY, JUNE 26, 2007
Contact: Elizabeth A. Thomson, MIT News Office
Phone: 617-258-5402
Email: thomson at mit.edu

CAMBRIDGE, Mass.--An international team of researchers, including  
several from MIT, has developed a computational model that helps  
identify relationships between proteins and the enzymes that regulate  
them.

The work could help researchers understand the complex protein  
networks that influence human disease, including cancer. The  
researchers report their findings in the cover story of the June 29  
issue of Cell.

The new method, known as NetworKIN, can trawl through existing  
research data and use it to illuminate protein networks that control  
cellular processes. It focuses on enzymes called kinases, which are  
involved in many cell signaling pathways, including repair of DNA  
damage that can lead to cancer.

The model was developed by researchers from MIT, the Samuel Lunenfeld  
Research Institute of Mount Sinai Hospital in Canada and the European  
Molecular Biology Laboratory in Germany.

NetworKIN “gives us the tools to take the information we already have  
and begin to build a map of the kinase signaling pathways within the  
cells,” said Michael Yaffe, MIT associate professor of biology and  
biological engineering, a member of MIT's Center for Cancer Research  
(CCR) and one of the authors of the paper.

“By getting a network-wide view, multiple aberrant genes of kinase- 
controlled processes are more easily targeted,” said Rune Linding, a  
postdoctoral fellow with joint appointments through the CCR and Mount  
Sinai. “In the future, complex human diseases will be treated by  
targeting multiple genes.”

Kinases act by phosphorylating, or adding a phosphate group, to a  
protein. That signal tells a protein what it should be doing. Yaffe  
estimated that at any one time, 30 to 50 percent of the proteins in a  
cell are phosphorylated.

Because kinases play such a critical role in cellular processes,  
including DNA repair and cell division, scientists have been working  
to identify where phosphorylation takes place in a target protein.  
Mass spectrometry makes it easy to identify those sites, but until  
now there has been no good way to figure out which kinases are acting  
on each site, Yaffe said.

“It's a huge bottleneck,” he said. “We're getting thousands of  
phosphorylation sites, but we don't know which kinase phosphorylated  
them, so we don't know what pathway to put them in.”

To solve that problem, the researchers developed a two-step approach.

In the first step, they used a pair of previously developed computer  
programs that can analyze the amino acid sequence of the  
phosphorylation site and predict which family of kinases is most  
likely to bind to and phosphorylate it.

However, each family includes several kinases, and the sequence alone  
cannot tell you which one acts on the site.

To pinpoint the kinases more accurately, the researchers developed a  
computational model that analyzes databases that contain information  
about signaling pathways and protein interactions. The program also  
performs “text mining” of published articles and abstracts to search  
for reported protein-kinase interactions.

By combining these two sources of information-sequences of the target  
proteins and contextual information about the interaction between  
proteins and kinases-the computational model can develop a detailed  
network that would be very difficult to create by manually examining  
the available data.

“The sequence gets us into the ballpark, but it's all of this  
contextual information that helps us figure out specifically which  
kinases are acting on which sites,” said Yaffe, who is also  
affiliated with the Broad Institute of MIT and Harvard, and Beth  
Israel Deaconess Medical Center.

Other MIT authors on the paper are Gerald Ostheimer, a postdoctoral  
fellow in biological engineering, Marcel van Vugt, a postdoctoral  
fellow at the Center for Cancer Research, and Leona Samson, director  
of the Center for Environmental Health Sciences and professor of  
biology and biological engineering.

The research was funded by the European Commission FP6 Programme, the  
Danish Research Council for the Natural Sciences, the Lundbeck  
Foundation, Genome Canada and the National Institutes of Health  
Integrative Cancer Biology Program.

--MIT--

Written by Anne Trafton, MIT News Office