Lewis Thomas Laboratory, 305
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.
Li Z, Stock JB. Protein carboxyl methylation and the biochemistry of memory. Biol Chem. 2009, 390:1097-1104.
Gordon JS, Wolanin PM, Gonzalez AV, Fela DA, Sarngadharan G, Rouzard K, Perez E, Stock JB, Stock MB. Topical N-acetyl-S-farnesyl-L-cysteine inhibits mouse skin inflammation, and unlike dexamethasone, its effects are restricted to the application site. J Invest Dermatol. 2008, 128:643-54.
Yongna Xing, Zhu Li, Yu Chen, Jeffry B. Stock, Philip D. Jeffrey, and Yigong Shi. Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell 2008, 133:154-63.
Chen Y, Xu Y, Bao Q, Xing Y, Li Z, Lin Z, Stock JB, Jeffrey PD, Shi Y. Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40. Nat Struct Mol Biol. 2007, 14: 527-34.
Chen Y, McQuade KJ, Guan XJ, Thomason PA, Wert MS, Stock JB, Cox EC. Isoprenylcysteine carboxyl methylation is essential for development in dictyostelium discoideum. Mol Biol Cell. 2007, 18:4106-18.
Xing Y, Xu Y, Chen Y, Jeffrey PD, Chao Y, Lin Z, Li Z, Strack S, Stock JB, Shi Y. Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell. 2006, 2002127: 341-353.
Vafai, S., and Stock, J.B. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer’s Disease. FEBS Lett. 2002, 518, 1-4.
Tolstykh, T., Lee, J., Vafai, S. and Stock, J.B. Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits. EMBO J. 2000, 19, 5682-5691.