PI3K signal and DNA repair: a short commentary

PI3K was originally discovered as a lipid kinase involved in the phosphorylation of the inositol ring in position -3, leading to the synthesis of phosphatidyl-inositol-3-4 bisphosphate. The enzyme purified from rat liver is an heterodimer of two subunits of 85 and 110 KD respectively: it phosphorylates the D3 hydroxyl of phosphoinositides to produce phosphatidyl-inositol-3-phosphate. So far the function of the 3-phospho-inositide is unclear. It is likely that the entire phospholipid serves as a second messenger, since no phospholipase C has yet been found that can cleave the inositol group with a 3 phosphate residue. However the activation targets of this second messenger are still poorly known. Recently a novel/serine/theronine kinase was insolated by three groups and called differently RAC, PKB and AKT. It exhibits sequence homology with protein kinase A and C at the carboxyl terminal, whereas the aminoterminal domain has a plectrin homology. Activation of ATK is inhibited by wortmannin, a specific inhibitor of PI3K at very low concentrations. Furthermore inositol-3-phosphate can activate ATK in vitro. In addition very recently, a linkage of G-protein coupled receptors to the MAP kinase signalled pattern through PI3K has been discovered. But what is downstream of this pathway? 70S6 kinase is an attractive candidate since this kinase, involved in protein synthesis, is activated by AKT in vivo. Interestingly AKT is the cellular protooncogene of v-ATK and this implies that ATK induces a pathway of oncogenic transformation. AKT is inhibited by dominant negative mutants of ras and thus involved in the ras-raf-MAP kinase pathway. The role of PI3K is still indefinite but it must have a paramount importance in cell signalling since nearly all growth factor receptors recruit this enzyme and that the activity of fundamental growth factor receptors like PDGF, EGF and insulin are blocked by the specific inhibitor wortmannin, leading to the conclusion that the PI3K signal is much important in mitogenesis, protein synthesis, membrane ruffling, cell transformation and cell cycle progression.