Mansilla, B.P.; (2005) Aspects of the control of polyphosphoinositide metabolism by ADP-ribosylation factors and diacylglycerols. Doctoral thesis , University of London.

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Abstract

In recent years, polyphosphoinositides, particularly phosphatidylinositol- 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), have become increasingly important due to the discovery that these lipids, rather than just having calcium or growth factor signalling functions, play key roles in a wide range of other important cellular processes. For this reason, their generation and control is tightly regulated by a growing group of enzymes that produce them, degrade them or depend on their presence to function. One of the main enzymes involved in PI(4,5)P2 production is Type I phosphatidylinositol 4-phosphate 5-kinase (PI(4)P5K), which generates it by phosphorylation of PI(4)P. PI(4,5)P2 is in the central fork of phosphoinositide cascades, from where several second messengers are generated. Its production by Type I PI(4)P5K is regulated, amongst others, by members of the small GTP binding protein family of ADP-ribosylation factors or ARFs. Part of my thesis has concentrated on determining the isoform selectivity between ARFs and lipid kinases, and the finding that ARF6, the most divergent isoform of the six known ARFs, is the preferred regulator. Previous studies have always defended the indiscriminate activation by both ARF1 and ARF6. This is the first time that a clear preference for ARF6 is proved in vitro and supported in permeabilised cell- systems. The activity of Type I PI(4)P5K has been known to be influenced by the presence of certain lipids, which either activate it, phosphatidylserine and phosphatidic acid, or inhibit it, as it happens by its own product, PI(4,5)P2.1 have found that another important cell signalling lipid, diacylglycerol, is also capable of activating the lipid kinase. Finally, one of the functions of PI(4,5)P2 is the generation of the second messenger PI(3,4,5)P3, by the subsequent phosphorylation of the inositol ring by phosphoinositide 3-kinases (PI3Ks). This lipid is involved in a very large number of crucial events in the cell, such as cell migration, cell survival and phagocytosis, amongst others. For the first time, I have found that ARF proteins are also involved in the generation of PIP3, by activating one of the four known isoforms of PI3K, namely pilOy.

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