title: The phosphatidylinositol 4-phosphate 5-kinase family.
abstract: The existence of a PIP5K family of enzymes has been suggested by Western blotting and purification of numerous PIP5Ks from various tissues and cell types. The erythrocyte has at least two PIP5Ks, named PIP5KI and PIP5KII, while the brain appears to have even more isoforms. The cloning of the first PIP5K, the PIP5KII alpha, is just the beginning of the molecular classification of this protein family. The PIP5KII alpha sequence has shown that these enzymes lack obvious homology to protein, sugar and other lipid kinases. The identification of two S. cerevisiae homologues, Mss4p and Fab1p, confirms that this family of kinases is widely distributed in eukaryotes. Not surprisingly, cloning experiments have identified additional isoforms. By cloning additional isoforms, insights into the structure and functions of this family of enzymes will be gained. One reason for a large family of PIP5Ks is that many forms of regulation and cellular functions have been ascribed to PIP5Ks, as summarized in Figure 10. Some of these functional links result from PtdIns[4,5]P2 being required for a given process, but the direct involvement of specific PIP5Ks is not well defined. Which PIP5K isoforms are regulated by a specific mechanism or are involved in a cellular process often is not clear. For example, which PIP5Ks produce PtdIns[4,5]P2 that is hydrolyzed by PLC or phosphorylated by the PI 3-kinase is not known. A few exceptions are PIP5KII not being able to phosphorylate PtdIns[4,5]P2 in native membranes, and PIP5KIs being stimulated by PtdA, required for secretion, and possibly regulated by G proteins of the Rho subfamily. The multiplicity of regulation and functions of each PIP5K isoform remains to be elucidated. Another factor governing the number of isoforms may be presence of multiple pools of polyphosphoinositides and the localizing of PIP5K function within cells. The polyphosphoinositides appear to be compartmentalized within cells and each pool appears to be sensitive to specific signals. These polyphosphoinositide pools may include those in the plasma membrane that are used by PLC, nuclear pools that appear to turn over separately from cytoplasmic pools and a small pool at sites of vesicle fusion with the plasma membrane. Each pool may be controlled by a specific PIP5K isoform. This would explain the diversity of PIP5K cellular roles. Another possibility is that the PIP5Ks are localized to certain areas of the cell by being part of a protein or proteolipid complex. Furthermore, the presence of PITP or PLC in the complex would potentially impart specificity and speed on the use of PtdIns[4]P and PtdIns[4,5]P2 because these lipids could be channeled quickly from one enzyme to the next. The concept of localized complexes containing particular PIP5K isoforms that control the composition of different polyphosphoinositide pools will likely be important as the family of PIP5K isoforms grows.
authors.affiliation: Department of Pharmacology, University of Wisconsin Medical School, Madison 53706, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Loijens
authors.forename: I V
authors.initials: IV
authors.lastname: Boronenkov
authors.forename: G J
authors.initials: GJ
authors.lastname: Parker
authors.forename: R A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D004912:Erythrocytes / Q000201:enzymology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010712:Phosphatidic Acids / Q000494:pharmacology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D017421:Sequence Analysis; D017386:Sequence Homology, Amino Acid
chemical_list: D010712:Phosphatidic Acids; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C037178:phosphatidylinositol 4-phosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D019204:GTP-Binding Proteins