An expanded view of inositol signaling

The long-range goal of our work is to elucidate how diverse extracellular stimuli elicit selective cellular responses through the activation of inositol polyphosphate (IP) signaling pathways. Defects in IP signaling pathways result in disease states such as Lowe syndrome, myotubular myopathy and cancer - through defects in the tumor suppressor PTEN. There are over 30 IP molecules, the majority of which have not been studied as messengers. It is our hypothesis that such IPs, designated as "orphans," may have important signaling roles. In support of this, we have recently defined novel roles for orphan IPs in regulating membrane trafficking, cytoskeletal organization, gene expression and mRNA export. These data indicate that cells are capable of producing multiple IP signals in response to stimulation. Thus, it seems plausible that individual agonists produce distinct patterns of IP signals, which thereby enable diverse cellular responses. Additionally, we have uncovered a family of lithium targets with relevance to manic depressive disease. An additional theme emerging from our work is that certain inositol signaling pathways are compartmentalized to the nucleus and directly effect nuclear function.