The phosphatidylinositol 4-phosphate 5-kinase family

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 PIP5KIIα, is just the beginning of the molecular classification of this protein family. The PIP5KIIα 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. ▪ FIG. 10. Summary of the regulation of the PIP5K isoforms and the cellular roles of PtdIns[4, 5]P 2 synthesized by these enzymes. One reason for a large family of PIP5Ks is that many forms of regulation and cellular functions have been ascribed to PIPSKs, as summarized in Figure 10. Some of these functional links result from PtdIns[4,5]P 2 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]P 2 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]P 2 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 the 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