MIT, Harvard, Yale, Dana Farber researchers: Enzyme 'atlas' helps researchers decipher cellular pathways

A team of researchers has mapped out more than 300 protein kinases and their targets, which they hope ultimately could result in new leads for cancer therapeutics.

Protein kinases are among the key classes of human enzymes and signal the molecules that regulate virtually all cellular actions, from cell division to growth and metabolism, and when these cellular pathways are not functioning properly, it can result in a range of diseases, including cancer, a Massachusetts Institute of Technology (MIT) news release said. 

A kinase is "A type of enzyme (a protein that speeds up chemical reactions in the body) that adds chemicals called phosphates to other molecules, such as sugars or proteins," a definition by the National Cancer Institute says. 

MIT researchers, led by Michael Yaffe, a David H. Koch Professor of Science, worked with professors Lewis Cantley of Harvard Medical School and Dana Farber Cancer Institute and Benjamin Turk of Yale School of Medicine to develop the detailed atlas of more than 300 protein kinases in human cells, the news release says. They were able to outline the proteins that kinases were likely to target and control, which could help determine the cellular signaling pathways and allow them to find out what happens to those pathways when cells turn cancerous or are targeted by a specific drug, the release said.

“We have a lot of sequencing data for cancer genomes, but what we’re missing is the large-scale study of signaling pathway and protein kinase activation states in cancer,” Yaffe said in the news release. “If we had that information, we would have a much better idea of how to drug particular tumors.”

While determining the protein kinases implicated in cellular dysfunction and cancer development could lead to new therapeutics, researchers don’t know exactly which cellular pathways are involved or what substrates they have, the release noted. Yaffe said in the release that a key has long been needed to detail the kinases that can phosphorylate (add phosphorus to) each of the 90,000 known phosphorylation sites that have been reported in human cells.

"For most of the phosphopeptides that are measured, we don’t know where they fit in a signaling pathway,” Yaffe said in the news release. “We don’t have a Rosetta stone that you could use to look at these peptides and say, this is the pathway that the data is telling us about. The reason for this is that for most protein kinases, we don't know what their substrates are."

The team of researchers examined two classes of kinases -- serine kinases and threonine kinases -- which comprise nearly 85% of the protein kinases in the human body. This, according to the release, is set by the type of structural motif they group the phosphate onto, the release says.

The researchers also discovered that a number of kinases have different amino acid sequences, according to the news release, and this can bind and phosphorylate the same motifs on their substrates. The researchers also found that about half of the kinases target one of three primary classes of motifs, and the other half target one of approximately 12 smaller classes, according to MIT.

The paper, which was published in the journal Nature, was authored jointly by Jared Johnson, an instructor in pharmacology at Weill Cornell Medical College, and Tomer Yaron, a graduate student at Weill Cornell Medical College. Yaffe and Cantley, who served as senior authors, have collaborated for 25 years, dating back to their work as postdocs in Cantley’s lab.

The researchers plan to use their results to seek new drug targets and develop better cancer treatments, the release says.