Indian Journal of Biochemistry & Biophysics Vol. 44, October 2007, pp. 289-294 Minireview Type II Phosphatidylinositol 4-kinase(s) in Cell signaling Cascades Ranjeet Kumar Sinha and Gosukonda Subrahmanyam* Biotechnology Group, School of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India Received 22 May 2007; revised 27 September 2007 Phosphorylated derivatives of phosphatidylinositol (PtdIns) are key components of many signaling cascades. Many isoforms of PtdIns kinases, PtdIns phosphate kinases and phosphatases use these lipids in amazing networks of signaling cascades that are yet to be understood fully. PtdIns 4-kinase(s) phosphorylates PtdIns at the 4 th –OH position of inositol head group and are classified in to type II and III PtdIns 4-kinases. While type III PtdIns 4-kinases are implicated in vesicular trafficking, type II PtdIns 4-kinases are suggested to play a role in cell signaling, cytoskeletal rearrangements, cell motility and in microbial pathogenicity. This paper reviews the role of type II PtdIns 4-kinases in cell signaling cascades in health and disease. Keywords: Lipid kinases; Cell signaling; Cytoskeleton; Cell adhesion; Microbial pathogenicity Introduction Phoshphatidylinositol (PtdIns) lipids are concentrated in cytosolic leaflet of eukaryotic cell membranes. The inositol head group of PtdIns is phosphorylated at the 3 rd , 4 th and 5 th -OH positions by a series of lipid kinases to generate PtdIns phosphates (Fig. 1). These kinases are classified as PtdIns 3-kinase(s), PtdIns 4-kinase(s) and PtdIns 5-kinase(s) based on their substrate specificity. These phosphorylated PtdIns lipids are further phosphorylated by PtdIns phosphate kinases. Among different phosphorylated derivatives of PtdIns lipids, PtdIns 4P, PtdIns 4,5P 2 , PtdIns 3,4P 2 and PtdIns3,4,5P 3 play a role in cell signaling cascades leading to motility, secretion, cell division and differentiation 1-10 . Biochemical characterization and molecular cloning of cDNA sequences have identified two families of PtdIns 4-kinases [EC 2.7.1.67] known as type II and III PtdIns 4-kinases 11-16 . Type II PtdIns 4-kinases have both membrane and cytosol localizations and are implicated in signaling mechanisms in immune cells and neuronal cells 9 . This paper reviews some of the recent developments on the role of type II PtdIns 4-kinases in PtdIns lipid signaling cascades in health and disease. PtdIns 4-kinases PtdIns 4-kinase(s) phosphorylates PtdIns at the 4 th –OH of the inositol ring (Fig. 1). The product PtdIns 4P serves as a precursor molecule for PtdIns 4,5P 2 , PtdIns 3,4P 2 and PtdIns3,4,5P 3 . It also interacts with many signaling protein molecules containing Pleckstrin Homology domains 10 . Pleiotropic functions of PtdIns4P suggest that PtdIns 4-kinases and phosphatases stringently regulate its levels both temporally and spatially by PtdIns 4-kinases and phosphatases. At least two families of PtdIns 4-kinases (type II and III) have been isolated on the basis of molecular mass, substrate specificity and sensitivity towards inhibitors (adenosine, wortmannin, Fig. 1—Phosphatidylinositol pathways to generate many phosphoinositides [Straight lines indicate identified pathways and dotted arrows indicate speculated pathways. The key step for PtdIns 4p generation by PtdIns 4-kinase (in bold)] _________ *Corresponding author: E mail:gsm@iitb.ac.in Ph: 91-22-25767777 (o); Fax: 91-22-25723480 Abreviations: aa, amino acids; EGF, epidermal growth factor; PtdIns, phosphatidylinositol; PtdIns 4P, phosphatidylinositol 4-phosphate; Ins(1,4,5)P 3, Inositol(1,4,5)tri-phosphate; PtdIns 4,5 P 2, phosphatidylinositol 4,5 bis-phosphate; TCR, T cell receptor.