Intracellular Signaling in Human Disease
My laboratory focuses on exploring and characterizing intracellular signaling pathways in the immune and nervous systems and identifying how defects/abnormalities can lead to disease. We employ modern techniques of cell and molecular biology and biochemistry to establish and test initial hypotheses and then validate our in vitro observations in both animal models and human derived material. Whenever possible we utilize non-transformed, primary cells as the starting point for our work.
Receptor-mediated signaling induced by a variety of agonists including cytokines (TGF-β1, IL-1 and GM-CSF/IL-5), small molecules (Ca2+), and cell-cell contact among others, triggers the rapid and sequential activation of tyrosine and serine/threonine (Ser/Thr) directed kinases. These kinases are pivotal to dynamic intracellular signaling, leading to changes in gene expression and ultimately appropriate cell and organ physiology. Curiously, when examined in vitro, protein phosphorylation often has modest effects on protein function. These results suggest that in vivo phosphorylation requires additional regulators or co-factors, presumably proteins that can sense phosphorylation changes and amplify signaling. One such regulator is Pin1. Pin1 is a highly conserved, ubiquitously expressed cis-trans peptidyl prolyl isomerase first described in 1996. It binds to phospho-Ser-Pro or phospho-Thr-Pro motifs via its N-terminal WW domain and isomerizes the intervening peptide bond via a C-terminal peptidyl isomerase domain.
Isomerization around this single bond alters the conformation of the target protein, leading to dramatic changes in function, location and/or stability. Pin1 has been implicated in a variety of critical processes involving Ser/Thr directed phosphorylation including cell cycle regulation, apoptosis, cytokine production and signaling and gene expression. Not surprisingly, dysregulation of Pin1 activity and/or expression has been implicated in the pathobiology, progression and prognosis of many human tumors including those from the breast, lung, gut or bone marrow. Pin1 knockout mice show a variety of pathology including premature aging, neuro-degeneration, infertility, reduced inflammatory and fibrogenic responses and reduced bone density. Paradoxically, Pin1 KO mice may also be “smarter” than WT as they show elevated post-synaptic protein synthesis.
Over the past 10 years, we have focused on elucidating the signaling cascades mediated by Pin1 in multiple normal and pathologic processes including asthma and allergic inflammation, cytokine production and signaling, cell death and the regulation of neuronal protein synthesis.