Focus

Membrane receptors and signal transduction

Research

We are primarily concerned with the development of novel pharmaceuticals to regulate signal transduction pathways that underlie chronic diseases associated with inflammation and aging. The activities of approximately a third of the proteins in vertebrate cells are regulated by reversible phosphorylation at serine and threonine resides. There are almost a thousand different protein kinases, each of which catalyzes the transfer of phosphoryl groups from ATP to a specific set of protein substrates in response to a regulatory input. In contrast, there are just a few phosphoprotein phosphatases to catalyze the removal of these groups. Our research over the past several years has focused on the molecular mechanisms that underlie the regulation of these phosphatases. Through these efforts we have identified potential pharmaceutical targets for the global regulation of phosphatase activity, developed screens for useful therapeutic agents, and characterized pharmaceutical leads that provide a basis for further medicinal chemistry exploration. Our current research is essentially translational, with two principal targets: skin and brain.

The skin project targets inflammatory diseases such as psoriasis, rosacea, atopic dermatitis, and acne as well as the general problem of skin aging. Our brain research is concerned with neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Both projects focus on the regulation and pharmacuetical modulation of the most abundant phosphoprotein phosphatase, phosphoprotein phosphatase 2A (PP2A). Several years ago we discovered that PP2A activity is regulated by reversible carboxyl methylation. This modification is catalyzed by two PP2A-specific converter enzymes, a methyltransferase (PPMT) and a methylesterase (PME). Demethylation is associated with inflammation, apoptosis, and neurodegeneration. We have identified several different pharmaceutical chemotypes that bind to PP2A and inhibit its demethylation by PME. We have shown that one agent, a natural product found in coffee, is efficacious in animal models for neurodegeneration and skin inflammation.

Biography

Jeffry B. Stock is a leading expert in signal transduction and global cellular regulation with over 150 original scientific articles in this and related areas. He is best known for his seminal work on membrane receptor function and signal transduction in micro-organisms. As a graduate student at Johns Hopkins in the early 70s he played a key role in elucidating the chemiosmotic relationships and bioenergetics of active transport and membrane receptor function in bacteria.   As a postdoctoral fellow at Berkeley and later as a Professor and independent investigator at Princeton, Dr. Stock has made numerous contributions toward understanding the molecular mechanism of sensory-motor regulation in prokaryotes. He was the first to elucidate the so-called two-component phosphorelay biochemistry that underlies sensory-motor regulation in specific, and serves generally to regulate bacterial responses to changing environmental conditions.

Although for most of his career Dr Stock’s research has focused on the basic biochemistry and molecular biology of cellular regulation; for the past decade he has been increasingly involved in translational research to apply the lessons derived from basic research to drug discovery and the development of useful therapeutics. Toward this end, Dr. Stock has founded several biotech startups including most recently the Signum Biosciences Group, for which he serves as Chairman. These efforts have lead to the development of topical anti-inflammatories for dermatological applications, as well as a novel systemic approach for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Dr. Stock has received numerous honors. He is an elected fellow of the American Academy of Microbiology and the American Association for the Advancement of Science, and a winner of the Humboldt Prize. He serves on the Centers Review Committee for the National Institute of Drug Abuse.

The Biochemistry of Memory