InterPro domain: IPR044769

This entry represents the C-terminal catalytic lipid kinase domain related to PtdInsP kinases (PIPKc domain) found in PIKfyve and related proteins.

1-phosphatidylinositol-3-phosphate 5-kinase ( 2.7.1.150 ), also called FYVE finger-containing phosphoinositide kinase (PIKfyve), forms a complex with its regulators, the scaffolding protein Vac14 and the lipid phosphatase Fig4. The complex synthesises phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] through the phosphorylation of phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) on the fifth hydroxyl of the myo-inositol ring. Then phosphatidylinositol-5-phosphate (PtdIns5P) is generated directly from PtdIns(3,5)P2. PtdIns(3,5)P2 and PtdIns5P regulate endosomal trafficking and responses to extracellular stimuli [ 1 ]. It is vital in early embryonic development and plays a role in different pathways, such as receptor tyrosine kinase (RTK) or EGFR degradation, regulation of the glutamate transporters EAAT2, EAAT3 and EAAT4 and the cystic fibrosis transmembrane conductance regulator (CFTR). It is also essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle [ 2 , 3 , 4 ].

The yeast orthologue of human PIKfyve, Fab1, is required for endocytic-vacuolar pathway and nuclear migration [ 5 , 6 ]. The plant orthologues such as FAB1A-D from Arabidopsis are important for the maintenance of endomembrane homeostasis and for development of viable pollen [ 7 , 8 ].

PIKfyve and its orthologues share a similar architecture consisting of a N-terminal FYVE domain, a middle region related to the CCT/TCP-1/Cpn60 chaperonins that are involved in productive folding of actin and tubulin, a second middle domain that contains a number of conserved cysteine residues (CCR) unique to these proteins, and a C-terminal catalytic lipid kinase domain related to PtdInsP kinases (or the PIPKc domain).

1. Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J. Biol. Chem. 282, 23878-91
2. ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality. J Mol Biol 384, 766-79
3. AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve. Sci Signal 6, ra45
4. Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching. Am J Physiol Endocrinol Metab 305, E119-31
5. Phosphatidylinositol 3-phosphate 5-kinase is required for the cellular response to nutritional starvation and mating pheromone signals in Schizosaccharomyces pombe. Genes Cells 7, 199-215
6. Phosphatidylinositol 3,5-bisphosphate regulates the transition between trans-SNARE complex formation and vacuole membrane fusion. Mol Biol Cell 30, 201-208
7. Arabidopsis FAB1A/B is possibly involved in the recycling of auxin transporters. Plant Signal Behav 6, 583-5
8. Arabidopsis FAB1/PIKfyve proteins are essential for development of viable pollen. Plant Physiol 151, 1812-22