My laboratory is interested in the molecular mechanisms by which the insulin receptor and other receptor tyrosine kinases (RTKs) are activated upon ligand binding, and the structural basis for recruitment of downstream signaling proteins to activated receptors. The main experimental technique we employ for three-dimensional structure determination is x-ray crystallography. Members of the RTK family include, among others, the insulin and insulin-like growth factor-1 (IGF1) receptors, fibroblast growth factor receptor, platelet-derived growth factor receptor, and epidermal growth factor receptor. RTKs play critical roles in signal transduction pathways that mediate cell proliferation, differentiation, migration and metabolism, both in organismal development and in adult homeostasis. RTKs have also been implicated in the onset or progression of numerous cancers.

Our group aims to understand the molecular mechanisms of secondary membrane transporter proteins using X-ray crystallography and cryo-electron microscopy. Secondary active transporters use a solute gradient to drive the translocation of ions, sugars, drugs, nucleosides, amino acids, or neurotransmitters, across the membrane. Many of such proteins are involved in the pathogenesis of diseases, and some are also drug targets. For example, both Prozac and cocaine exercise their effects by binding to secondary membrane transporters. Crystal structures of such proteins will directly reveal the substrate-binding site and the substrate-translocation pathway, and can suggest the conformational changes required for the substrate translocation.

Post-transcriptional processes play a crucial role in controlling gene expression in all organisms. Our research is aimed at elucidating the molecular mechanisms by which such control is imposed. We are particularly interested in two important means by which genes are regulated post-transcriptionally: messenger RNA degradation and repression by microRNAs and siRNAs. The goal of our investigations is to identify and characterize the proteins, RNA elements, and molecular mechanisms that govern these key regulatory processes in bacterial and mammalian cells.

The main focus of our lab is the study of proteins and their roles in cellular signaling events. While great strides in understanding intracellular signal transduction have been made in recent years by using molecular biological techniques, we feel that a more complete understanding of the dynamics of intracellular decision-making processes can be gained only by studying the proteins directly. We use mass spectrometry as the main tool for our studies because of the wide variety of information about protein structure it can provide while requiring only small amounts of protein for analysis.

Our lab focuses on membrane transport by ATP-dependent ion pumps and intercellular adhesion by cell-cell junctions. We use electron microscopy to determine 3D structures of proteins involed in these processes. For membrane transport, we use electron crystallography to study helical assemblies of Ca-ATPase and its relatives in the family of P-type ATPases. For intercellular adhesion, we use electron tomography to map the molecular architecture of desmosomes and adherens junctions in situ.

Extensive genetic information and new techniques to manipulate the genome of the mouse have led to its widespread use for studying development and modeling human diseases. In this rapid proliferation of methods to genetically engineer mice, in vivo technologies to analyze anatomical structure and function in the mouse have not kept pace. The results of transgenic and gene targeting experiments are usually analyzed using histological methods, which are static and two-dimensional, making it difficult to understand the underlying developmental and disease processes, which are dynamic and three-dimensional. We are developing both ultrasound and magnetic resonance micro-imaging approaches to provide noninvasive, dynamic structural and functional data on developmental and disease processes in mice.