INO-PYROPHOSPHATES · Inositol Pyrophosphates: a novel class of cellular messengers
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-06-01 → 2007-05-31
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
Lines connect the coordinator with its partners.
Results in brief
Final Activity Report Summary - INO-PYROPHOSPHATES (Inositol Pyrophosphates: a novel class of cellular messengers)
Numerous inositol phosphates occur ubiquitously in biological tissues. Inositol hexakisphosphate (IP6, also known as phytic acid) is by far the most abundant inositol polyphosphate in eukaryotic cells. The fully phosphorylated inositol ring of IP6 is the precursor of a completely new class of inositols, the inositol pyrophosphates. The six phosphorylated carbons that comprise the IP6 ring can be further phosphorylated creating more polar inositol polyphosphates that contain one or two high energy pyro-phosphate bonds IP7 and IP8. The aim of my laboratory is to study the physiological role of inositol pyrophosphates. Thanks to the Marie Curie International Reintegration Grant that was instrumental for establishing my laboratory at the MRC Laboratory for Molecular Cell Biology (LMCB), within the campus of University College London (UCL), we have advanced our understanding of inositol pyrophosphate biology. First we developed new techniques important for the analysis of this new class of cellular messengers. Thanks to this technological vantage we were able to demonstrate that IP7 and IP8 can directly phosphorylate proteins more important recently we published a new work demonstrating that IP7 is able to transfer the phosphate to a previously phosphorylated serine in new kind of post-transduction modification protein pyrophosphorylation. We have accumulated evidence that this new signal transduction paradigm is important for controlling intracellular vesicular trafficking. To understand as this mechanism is regulated we need to understand where and when IP7 is synthesised identifying the factors controlling IP6Ks (the enzymes responsible for IP7 synthesis). We have employed a Yeast Two Hybrid (YTH) to identify IP6Ks interacting proteins that likely will regulate the localization and activity of the IP6K. We believe that the analysis of IP7-dependent signalling mechanism in eukaryotic cells will dramatically increase the level of interest in the field, opening the opportunity for very unique and potentially ground-breaking discoveries.
Data: CORDIS, © European Union
Project objective
Several phosphorylated derivatives of myo-inositol are present in eukariotic cells, the most abundant of these being the fully phosphorylated inositol hexakisphosphate (IP6). IP6 is the precursor of a new class of more polar inositol polyphosphates containing one or two high-energy pyrophosphate bonds.The best characterized inositol pyrophosphates are the diphosphoinositol pentakisphosphate (IP7 or PP-IP5) and the bis-diphosphoinositol tetrakisphosphate (IP8 or [PP]2-IP4). IP7 and IP8 are present in all eukaryotic cell analyzed thus far, from the amebae Dictyostelium to mammalian neurons, and the enzymes responsible for their synthesis are highly conserved throughout evolution.The high-energy bonds present in IP7 and IP8 have the potential for unprecedente d molecular actions and their unique structure suggests that inositolpyrophosphates represent a new class of messengers with basic and not yet fully characterized functions. The cloning of the IP6 kinases (IP6K), the enzymes responsible for the synthesis o f inositol pyrophosphates, has provided me with the opportunity of obtaining the molecular tools necessary for studying inositol-pyrophosphate-mediated signalling.Using recombinant IP6K, I was able to synthesize radiolabelled IP7 of high specific activity. Our recent exciting results demonstrate that IP7 acts as a phosphate donor in a novel mechanism of protein phosphorylation. It is my intention to expand and further characterize the means by which inositol pyrophosphates regulate cell functions by combining biochemical, molecular and genetic approaches.Moreover, I will spend considerable effort in developing new methodology for the detection of inositol pyrophosphates in vivo. I believe that a simple and reliable technique enabling the analysis of IP7-dependent signalling in eukaryotic cells will dramatically increase the level of interest in the field, opening the opportunity for very unique and potentially groundbreaking discoveries.
Original text from CORDIS.
Participants
- MEDICAL RESEARCH COUNCIL · LONDONCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union