PIKfyve

The phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of PtdIns(3,5)P2, that has been implicated in various trafficking events associated with the endocytic pathway.

1232221-74-7
APY0201
1232221-74-7
371942-69-7
YM-201636
371942-69-7

Background


An overview of PIKfyve

PIKfyve, an evolutionarily conserved large protein and a product of a single-copy gene from yeast through plants to mammals, is one of the best examples of a PI-binding/PI-synthesizing enzyme; it associates with membrane PtdIns3P, synthesizing PtdIns(3,5)P2 and PtdIns5P. Given the functional outputs of PIKfyve activity, it is conceivable that the enzyme controls diverse cellular processes. The best characterized role of PIKfyve is within the endosomal/endocytic system, first recognized by the ability of the kinase-deficient PIKfyveK1831E mutant to induce progressively exacerbated cytoplasmic vacuolation in many cell types, including COS, HeLa, HEK293, fibroblasts and CHO. Mammalian PIKfyve is a member of an evolutionarily ancient gene family of PtdIns(3,5)P2-synthesizing enzymes that are large proteins, represented by a single-copy gene in most, if not all, species with sequenced genomes. Mouse PIKfyve, named so after its function and domain structure (PhosphoInositide Kinase for five positions containing a Fyve finger) was the first among the PtdIns(3,5)P2-synthesizing enzymes in higher eukaryotes to be identified. It was cloned from a mouse F442A adipocyte library through a screen for transcripts that, like the GLUT4 transporter, are enriched in fat and muscle.

Inhibition of PIKfyve

Phosphoinositides have crucial roles in cellular controls, many of which have been established through the use of small-molecule inhibitors. Due to the dynamic nature of many transport pathways that may be regulated by PtdIns(3,5)P2, the inhibitor of PIKfyve would be a meaningful tool for studying the acute effects of preventing the synthesis of PtdIns(3,5)P2 and the recovery process. Several kinds of PIKfyve inhibitors have been reported to show inhibition effect in different cell lines, such as YM-201636, MF4 and APY0201. YM-201636 inhibits PIKfyve mainly by affecting the maturation of lysosomes and autophagosomes. The inhibition of PIKfyve by MF4 mainly affects the rate of consumption of autophagosomes. APY0201 is a potentially highly selective ATP-competing PIKfyve kinase inhibitor.

PIKfyve and diseases

Possibly owing to impaired normal endosomal processing and membrane excretion from the endosome, PIKfyve dysfunction will cause endosomal enlargement and deep cytoplasmic vacuolation. Besides, PIKfyve is essential for the synthesis of phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] and for the regulation of endolysosomal membrane dynamics in mammals and PtdIns(3,5)P2 deficiency causes neurodegeneration in mice and humans.

References:

Harold B.J. Jefferies (2008). A selective PIKfyve inhibitor blocks PtdIns(3,5)P2 production and disrupts endomembrane transport and retroviral budding, 9,164-170.

Assia Shisheva (2008). PIKfyve: Partners, significance, debates and paradoxes, 32,591-604.