Of yeast and men. The evolution of PtdIns(3,4,5)P(3) synthesis.

Abstract

Since the identification of the lipid second messenger phosphatidylinositol (3,4,5)‐trisphosphate (PtdIns(3,4,5)P3; Traynor‐Kaplan et al , 1988; Auger et al , 1989), this molecule has become a paradigm for how phosphoinositides (PIs) mediate complex signalling events in cells. PtdIns(3,4,5)P3 can regulate chemotaxis, cell survival, translation and cytoskeletal rearrangement (Cantley, 2002), the deregulation of which contributes to the pathology of diseases such as diabetes, and breast and prostate cancer. PtdIns(3,4,5)P3 is a phosphorylated form of the PI phosphatidylinositol (PtdIns). All PIs have two fatty‐acid chains that anchor them to membranes and a hydrophilic inositol head group that is exposed to the aqueous cytosol (Fig 1A). This head group can be phosphorylated at the 3‐, 4‐ and 5‐positions and so far, a total of seven phosphorylated derivatives of PtdIns have been reported (Fig 1A). Figure 1. Pathways of PtdIns(3,4,5)P3 synthesis. ( A ) Phosphatidylinositol (PtdIns) is the basic building block of phosphorylated phosphoinositides (PIs). The inositol head group can be phosphorylated in the 3‐, 4‐ and 5‐positions to generate derivatives of PtdIns, which are listed on the right. (B) Schematic for receptor‐driven PtdIns (3,4,5)‐trisphosphate (PtdIns(3,4,5)P3) production. Agonist stimulation (tyrosine kinase or G‐protein‐coupled receptors) activates class I PI 3‐kinase to induce phosphorylation of PtdIns(4,5)P2 on the 3‐position of the inositol group. (C) The proposed new pathway for PtdIns(3,4,5)P3 production in Schizosaccharomyces pombe . Fission yeast enzymes are shown in blue. Their mammalian counterparts are depicted in turquoise. PIP 5‐K, phosphatidylinositol‐4‐phosphate 5‐kinase; PTEN, phosphatase and tensin homologue. After the treatment of cells with certain agonists, the transient synthesis of PtdIns(3,4,5)P3 is initiated by …