My laboratory is interested in the biology of cellular
communication networks and the mechanisms by which
defects in these pathways contribute to the pathophysiology
of human disease. We study a widely utilized communication
network, the inositol signal transduction pathway.
The classic paradigm of inositol signaling activation
is that receptor stimulation leads to the breakdown
of an inositol lipid precursor into two second messengers
inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol,
which regulate calcium release and protein kinase
C, respectively. However, in recent years the tremendous
complexity of the inositol metabolic pathway has become
evident. Diverse stimuli from growth factors to light
activate molecular programs that lead to the production
of numerous inositol polyphosphate (IP) messenger
molecules. In all, over 30 lipid and water-soluble
IP molecules have been identified in eukaryotic cells,
many of which have not yet been assigned a function
in cells and hence have been designated as “orphan”
IP molecules.
Our research effort focuses on expanding the paradigm
of inositol signaling by seeking to identify the cellular
targets and processes influenced by "orphan"
IP messengers. We utilize a multidisciplinary approach,
which includes Pharmacology, Biochemistry, Genetics,
Biophysics and Cell Molecular Biology, that has enabled
us to characterize the function of over ten gene products
that regulate the synthesis and breakdown of these
molecules. Our work has helped identify new roles
for “orphan” IP messengers in the regulation
of diverse processes including membrane trafficking,
cytoskeletal organization, gene expression, and mRNA
export. Furthermore, we have found that an additional
layer of complexity is achieved through the compartmentalization
of IP pathways to the nucleus. In addition, by determining
the X-ray crystal structure of one of the enzymes
we have uncovered a novel family of lithium targets
with relevance to manic depressive disease. These
discoveries have led to a revision of the classic
paradigm of inositol signaling to include several
new inositol second messengers and have uncovered
new areas of research aimed at understanding a fundamental
problem in biology – that of how diverse stimuli
utilize IP signaling pathways to achieve specific
cellular responses.
