Cell signalling by inositol pyrophosphates

The cells of our body are required to communicate and coordinate external inputs, such as nutrient availability or hormone levels, in order to behave properly. In cells information is collected and spread through molecules, via changing of their amounts and locations. Loss of control of these complex cellular processes leads to pathological conditions and human diseases. We aim to understand how information is created, stored and communicated inside cells and throughout our bodies by studying a certain collection of these “signalling” molecules: the inositol phosphates. This family comprises a number of molecules that are found in all organisms, and are essential for correct cell health and behaviour. So far we know that inositol phosphates are involved in coordinating the use of the important nutrient phosphate, but we are still working to understand how this is achieved. The amounts and roles of inositol phosphates are altered in pathological conditions such as diabetes and obesity; the ultimate goal is to fix these problems at a cellular level, and thus help patients.

Living cells are required to communicate and coordinate external inputs and internal needs in order to behave appropriately. Intracellular cell signalling networks coordinate cellular physiology by integrating and disseminating information. Understanding how this information is elaborated, stored and transduced represents one of the most fascinating aspects of biology. Inositol phosphates (IP), found as both lipid-bound and cytosolic isoforms, represent one of the most complex cell signalling systems. We are studying the inositol phosphate network with the aim of understanding the molecular logic of cellular signalling. Investigation into cellular regulation by IP has yielded surprising knowledge that reaches well beyond the established roles of IP3 (as calcium releasing factor) and PIP3 (as AKT activator). Indeed, I am interested in studying the numerous ‘non-classical’ aspects of the IP regulatory system. My primary interest is in the inositol pyrophosphates (PP-IPs), molecules which have not yet been fully characterised but are known to contain a high energetic pyrophosphate moiety, that are important controllers of cellular homeostasis and energetic metabolism. In comparison to the IP3/calcium or PIP3/AKT signalling paradigms, PP-IPs signalling is evolutionarily ancient, present in all eukaryotic organisms. The past ten years of research have positioned PP-IPs at the interface between metabolism and signalling, indicating that they are involved in the pathogenesis of important metabolic disorders like obesity and diabetes. Inositol pyrophosphates, by altering phosphate homeostasis, affect basic energetic metabolism and the synthesis of ATP and other phosphate-rich molecules such as inorganic polyphosphates (polyP). In spite of their clear relevance for a number of fundamental cellular functions, many aspects of the PP-IPs mode operandi remain poorly understood. Our research aims to fill this gap in knowledge by investigating how PP-IP levels are regulated, and elucidating the cross-talk between PP-IPs, polyP and ATP.
To appreciate the importance of PP-IPs and of the complex IP signalling system in general, we should realise that the entire IP network of molecules is metabolically connected. Therefore, understanding how this network of molecules evolved and became one of the fundamental signalling systems of eukaryotic cells may also help us understand the evolutionary pressures that created us.