The Role of Inositol Signaling in Human Disease

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DESCRIPTION(adapted from applicant's abstract): The long-range goal of this project 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 human oculocerebrorenal syndrome or Lowe syndrome. There are over 30 IP molecules the majority of which have not been studied as messengers. It is our hypothesis that such IPs, designated a "orphans," may have important signaling roles. In support of this, we have recently defined novel signaling roles for orphan IPs in regulating membrane trafficking, cytoskeletal organization, gene expression and mRNA export. Additionally, we have uncovered a family of lithium targets with relevance to manic depressive disease. A new theme emerging from our work is that certain inositol signaling pathways are compartmentalized to the nucleus and directly effect nuclear function. This project focuses on the roles of orphan IF messengers in regulating, membrane trafficking, gene expression and messenger RNA export. We also seek to characterize a new family of I phosphatases that are potential targets of lithium relevance to bipolar disease. IP5 and IP6 are ubiquitous inositol phosphates that until our recent work had no clearly defined roles as signaling molecules. We have shown that PLC produces IP3, which is then sequentially phosphorylated to IP6 by two IP kinases, a nuclear dual-specificity IP3/IP4 kinase (Ipk2), and nuclear envelope/pore complex localized IP5 2-kinase (Ipkl). Ipk2p reveal is identical to a known transcription factor providing a crucial direct link of IP signaling and gene expression. Understanding the target genes regulated by Ipk2p-mediated transcription complexes, the IP receptors and the mechanism by which localized production of IP4/IP5 mediate changes in transcription will help define how nuclear IP signals regulate cell growth and development. Studies of Ipklp have uncovered a role for IP6 production in messenger RNA export Identification of the receptors, components involved and mechanisms of regulation will be instrumental in elucidating how IP signaling regulates messenger RNA export. We also plan to evaluate the function of IP5 and IP6 in mammalian systems. Do they serve a similar function to that in yeast? We plan to isolate and clone cDNA's encoding the enzymes that interconvert IP5 and IP6 in mammalian tissues namely IP5 2-kinase and IP6 2-phosphatase in order to determine how production of these metabolites is controlled. In addition, we plan to study the first dual-functional inositol lipid phosphatase with two autonomous active sites, one a polyphosphoinositide phosphatase and the other a 5-phosphatase similar to the OCRL-l protein that is mutated in Lowe syndrome.