Cellular signaling systems with emphasis on heterotrimeric G proteins

Our laboratory is interested in the study of cellular signaling systems with special emphasis on signaling through heterotrimeric G proteins. We are interested in understanding how signals are routed and processed through cellular signaling networks including mechanisms of information sorting and integration. We are interested in understanding dynamics of network topology. For this we focus on identifying regulatory motifs such as feedback and feedforward loops and determining their information processing capability. We have constructed and analyzed dynamic maps of these motifs to understand how cellular signaling networks engage the various cellular machinery to produce physiological responses to extra-cellular signals. To study complex cell signaling networks we utilize a combination of experimental and theoretical approaches. Multidimensional experimental approaches currently being used in the laboratory include reverse-phase phosphoproteomic arrays, transcription factor arrays, and microarrays to obtain message profiling. These experimental approaches are being integrated with theoretical analysis using both graph theory approaches and differential equation based modeling to understand network regulation of cell proliferation and activity induced synaptic plasticity.

We are interested in understanding how spatial organization within the cell contributes to information processing within signaling networks. For these studies at the experimental level we are developing approaches to observe and quantify biochemical signaling reactions in live cells. At the computational level we are analyzing signaling networks using systems of ordinary and partial differential equations. We are developing spatially realistic models of signaling networks to understand the origins and dynamics of microdomains of signaling components.

We are developing approaches to use cell signaling components as therapeutic agents. In these studies we are testing if interactions between signaling pathways can be used as a basis for therapy. Here we seek to integrate experimental and theoretical approaches to identify potential drug targets in a hierarchical manner and develop small molecule interactors with these targets. At the molecular level we study how G protein subunits regulate effectors and the structural features of the domains involved in interactions between G protein subunits and effectors. We have identified regions on adenylyl cyclases (AC) that are involved in receiving signals from Gβγ subunits. We are also analyzing regions of adenylyl cyclase involved in receiving signals from Gα_s. We have identified regions of Gβ involved in transmitting signals to adenylyl cyclases and phospholipase C-β. These regions have been analyzed in detail to identify general binding regions and signal transfer regions within areas involved in effector contact. We are analyzing these regions by the use of combinatorial approaches to identify key residues and evaluate positional importance of these residues and the selectivity necessary to achieve local conformational changes as measured by NMR. From these studies we seek to understand the general rules by which selectivity in protein-protein interactions is achieved and how interactions between discrete regions result in signal transfer from G proteins to effectors.