P13K SIGNAL AND DNA-REPAIR - A SHORT COMMENTARY

PI3K was originally discovered as a lipid kinase involved in the phosp horylation of the inositol ring in position -3, leading to the synthes is of phosphatidyl-inositol-3-4 bisphosphate [1]. The enzyme purified from rat liver is an heterodimer of two subunits of 85 and 110 KD resp ectively: it phosphorylates the D3 hydroxyl of phosphoinositides to pr oduce phosphatidylinositol-3-phosphate [2]. So far the function of the 3-phospho-inositide is unclear. It is likely that the entire phosphol ipid serves as a second messenger, since no phospholipase C has yet be en found that can cleave the inositol group with a 3 phosphate residue [2]. However the activation targets of this second messenger are stil l poorly known. Recently a novel/serine/theronine kinase was insolated by three groups [3-6] and called differently RAG, PKB and AKT. It exh ibits sequence homology with protein kinase A and C at the carboxyl te rminal, whereas the aminoterminal domain has a plectrin homology. Acti vation of ATK is inhibited by wortmannin, a specific inhibitor of PI3K at very low concentrations [7]. Furthermore inositol-3-phosphate can activate ATK in vitro [8]. In addition very recently, a linkage of G-p rotein coupled receptors to the MAP kinase signalled pattern through P I3K has been discovered [9]. But what is downstream of this pathway? 7 0S6 kinase is an attractive candidate since this kinase, involved in p rotein synthesis, is activated by AKT in vivo [8]. Interestingly AKT i s the cellular protooncogene of v-ATK [3] and this implies that ATK in duces a pathway of oncogenic transformation. AKT is inhibited by domin ant negative mutants of ras and thus involved in the ras-raf-MAP kinas e pathway. The role of PI3K is still indefinite but it must have a par amount importance in cell signalling since nearly all growth factor re ceptors recruit this enzyme [2] and that the activity of fundamental g rowth factor receptors like PDGF, EGF and insulin are blocked by the s pecific inhibitor wortmannin [10], leading to the conclusion that the PI3K signal is much important in mitogenesis, protein synthesis, membr ane ruffling, cell transformation and cell cycle progression. (C) 1997 The Italian Pharmacological Society.