Inside the 10 trillion cells of the human body, a vast communications network hums under the control of some 70,000 proteins, orchestrating everything from memory to immunity. Amid this cacophony, scientists have struggled to tune in the distinctive chemical tones of the kinases: a large family of signaling molecules that are critical for almost all cellular activity.
Kevan Shokat has marshaled the resources of chemistry, protein engineering, and genetics to solve this significant biological challenge and provide scientists with the tools they need to understand the function of individual kinases within a cell. All kinases work by transferring energy, in the form of a phosphate, from adenosine triphosphate (ATP)—a molecule that stores energy for the cell, much like a battery—to other proteins. But since roughly 600 kinases exist, the challenge lies in focusing on a specific one.
Shokat has devised an approach to solve that problem, using chemical genetics to decipher individual kinases and their cellular signaling networks. His goals are to understand each kinase's role in the body and to learn which kinases would be good candidates for drug development. His lab currently is working to identify kinases that may play a role in asthma, diabetes, some forms of cancer, neurological disorders, bacterial infections, drug addiction, and chronic pain.
Using his chemical-genetics approach, Shokat mutates a particular kinase of interest and then designs a labeled molecule, or substrate, that only binds to the mutated kinase. Thus, specific kinases can be tagged and tracked along their signal transduction pathways inside cells. Shokat's lab also has developed a "knockout" technique to shut down, or inhibit, one specific kinase at a time, allowing researchers to study the effect on cell signaling. Over the past seven years, scientists have used these chemical-genetics techniques to study more than 70 protein kinases involved in a wide range of jobs inside the cell.
In a separate project, Shokat has developed a method to map the locations on proteins where phosphates bind inside cells. By pinpointing bond locations, scientists could correlate bond patterns with disease. Drugs might be designed to block a particular kinase before it carries phosphate to a specific bond site.
Ultimately, Shokat's chemical-genetics strategy could lead to a map of the "phosphoproteome," the complete set of all protein kinase substrates in the body. The tools also promise to reveal the workings of other important protein families, such as myosin motor proteins, lipid kinases, and deyhdrogenases, which Shokat's lab also has begun to study.
Dr. Shokat is also Professor and Chair of Cellular and Molecular Pharmacology at the University of California, San Francisco, and Professor of Chemistry at the University of California, Berkeley.
RESEARCH ABSTRACT SUMMARY:
Kevan Shokat has developed chemical methods to decipher the role of individual kinases and their cellular signaling networks. His goals are to understand each kinase's role in the body and to learn which kinases should be targeted to treat diseases such as cancer and immune dysfunction.
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Photo: George Nikitin/AP, © HHMI