Nancy L. Allbritton
Signal Transduction by Second Messengers and Protein Kinases
Organisms utilize phosphoinositide (PI) and Ca2+ signaling pathways to control a diverse array of functions, ranging from fertilization and development to vision and synaptic plasticity. Defects in PI and Ca2+ signaling are implicated in the pathogenesis of a wide range of diseases including birth defects, mental illness, and cancer. Measurements on single cells have revealed a complex spatiotemporal pattern of Ca2+ signaling. Nearly all activated eukaryotic cells exhibit repetitive spikes in their intracellular Ca2+ concentration, suggesting that this process is fundamentally important in signal transduction. There is evidence thatsimilarly complex spatial or temporal patterns might occur for other second messengers such as diacylglycerol(DAG), inositol 1,4,5-trisphosphate (IP3), and cAMP. The ultimate goal of the research is to understand how these complex patterns of second messengers are generated, and how they regulate cellular processes such as gene transcriptionS motility, and metabolism. Current research focuses on: 1) understanding how Ca2+ spikes and waves are generated by IP3 and other second messengers, 2) determining how nuclear concentrations of Ca2+, IP3 and DAG are regulated and consequently control nuclear functions, and 3) deciphering how Ca2+ spikes regulate the activity of kinases and phosphatases and ultimately cellular activities. To address these questions, novel techniques are being developed to measure the concentrations of second messengers, and the level of substrate phosphorylation in single cells.