Education
Ph.D. 1993, University of Pennsylvania
Research
The initial intracellular response to many external stimuli, including hormones, growth factors, and neurotransmitters, involves activation of a membrane phospholipid-hydrolyzing enzyme, phospholipase C- ß3 (PLC-ß) whose product second messengers mobilize intracellular calcium and activate protein kinase C (PKC) leading to a wide variety of cellular responses. I am interested in the regulation of phospholipid-dependent signal transduction from the level of the receptor through the effector enzyme PLC-ß Protein phosphorylation is a common modification employed by cells to alter protein function. We hypothesize that phosphorylation by activated protein kinase C performs a negative feedback role in phospholipid-dependent signaling to alter the function of some or all of the proteins in the signaling pathway. Using purified signaling proteins and protein kinases we have been studying the phosphorylation of PLC-ß enzymes in detail at a molecular level. I hope to begin making phosphorylation-site deficient mutants of PLC-ß and studying the effect of mutations in an intracellular context. Elucidation of the mechanisms underlying a decreased responsiveness (desensitization) in signaling pathways is important for a complete understanding of cellular responsiveness. Signal desensitization can be a mechanism to avoid cell over-stimulation. Conversely, de-regulated signaling pathways are responsible for some kinds of malignant cell transformation. Clinically, targets for lengthening the duration of action of therapeutics may be designed based on a better understanding of desensitization of signal transduction pathways.
