The research efforts of our laboratory have focused on understanding the molecular mechanisms by which signals are transmitted from cell surface receptors to biological effectors.  Four complimentary areas of research are currently being pursued in the laboratory. 

 

First Area of focus

Involves studies of the regulation and structural characterization of the Ras-related G protein, Cdc42, and related Rho GTPases.  These G proteins and their regulators play critical roles in cell growth, the establishment of cell polarity, and cytokinesis.  We have been particularly interested in examining the roles of Cdc42 and its signaling partners in mammalian development, and in particular, in neurogenesis. 

PDB: 1DOA

PDB: 1DOA


second area of focus

Involves delineating the signals from Rho GTPases and various oncogenic proteins that impact the metabolic machinery of cancer cells.  We have been especially focused on understanding the signaling regulation of a key metabolic enzyme that is responsible for the “glutamine addiction” exhibited by cancer cells undergoing the “Warburg effect”, and in the development of small molecule inhibitors into drug candidates.

PDB: 5HL1

PDB: 5HL1


Third area of focus

A third area of research focuses on structure-function comparisons between heterotrimeric G proteins, Ras-like G proteins, and the GTP-binding protein/protein crosslinking enzyme, transglutaminase. We have used the retinal G protein, transducin, as a model for obtaining structural pictures of how G protein-coupled receptors engage and signal through heterotrimeric (large) G proteins.  We are combining fluorescence spectroscopic approaches with X-ray crystallography, small angle X-ray scattering, another structural methods to analyze the three dimensional structures of the G protein-coupled receptor, rhodopsin, bound to wild-type transducin or different novel transducin mutants.

Eye of rhodopsin

FOURTH AREA OF FOCUS

A fourth area of focus in the laboratory concerns the biochemistry and clinical relevance of extracellular shed vesicles (microvesicles and exosomes).  These vesicles, which are generated in response to different extracellular cues, contribute to a number of different aspects of cancer progression, as well as to the actions of embryonic stem cells.  We are trying to determine how these vesicles are loaded with specific protein and nucleic acid cargo, whether we can block their production and/or shedding, and if this will provide new strategies of therapeutic intervention.