PHOSPHATIDYLINOSITOL 4-KINASES

Polyphosphoinositides are involved in many signal transduction pathway s in eukaryotic cells. The first committed step is catalysed by phosph atidylinositol 4-kinase leading to the formation of phosphatidylinosit ol 4-phosphate. In the last four years, ten cDNA molecules have been c loned which code isoforms of phosphatidylinositol 4-kinase: some of wh ich are highly related. Characteristically, they contain a C-terminal catalytic domain which is similar to that of (poly)phosphoinositide 3- kinases and to that of more distantly related lipid/protein kinases. A lignment has characterised cDNAs from Caenorhabditis, Dictyostelium an d Schizostaphyloccus pombe as those of phosphatidylinositol 4-kinases also. All these lipid kinases are related to the superfamily of protei n kinases. Several amino acids are highly conserved in catalytic domai ns of lipid and protein kinases. Employing the catalytic subunit of th e cAMP-dependent protein kinase as template, these residues can be ass igned functionally. On the basis of the alignment, a phylogenetic tree of the superfamily of phosphatidylinositol kinases has been construct ed. Three families, the phosphatidylinositol 4-kinases, phosphoinositi de 3-kinases, and the phosphatidylinositol related lipid/protein kinas es, carl be recognised. Each family comprises two subfamilies. The inv olvement of the phosphatidylinositol 4-kinases in signal transduction processes is summarised and a new hypothesis for the function of their isoforms in polyphosphoinositide signalling is presented. The involve ment of phosphatidylinositol 4-kinases in formation of lipid-protein i nteractions with cytoskeleton proteins and the metabolism of polyphosp hoinositide in the nucleus is discussed.