PIKFYVE

PIKfyve, a

The principal enzymatic activity of PIKfyve is to phosphorylate PtdIns3P to PtdIns(3,5)P2. PIKfyve activity is responsible for the production of both PtdIns(3,5)P2 and phosphatidylinositol 5-phosphate (PtdIns5P).^{[7][8][9][10]} PIKfyve is a large protein, containing a number of functional domains and expressed in several spliced forms. The reported full-length mouse and human cDNA clones encode proteins of 2052 and 2098 amino acid residues, respectively.^{[6][11][8][12]} By directly binding membrane PtdIns(3)P,^[13] the FYVE finger domain of PIKfyve is essential in localizing the protein to the cytosolic leaflet of endosomes.^[6][13] Impaired PIKfyve enzymatic activity by dominant-interfering mutants, siRNA- mediated ablation or pharmacological inhibition causes lysosome enlargement and cytoplasmic vacuolation due to impaired PtdIns(3,5)P2 synthesis and impaired lysosome fission process and homeostasis.^[14] Thus, via PtdIns(3,5)P2 production, PIKfyve participates in several aspects of vesicular dynamics,^[15][16] thereby affecting a number of trafficking pathways that emanate from or traverse the endosomal system en route to the trans-Golgi network or later compartments along the endocytic pathway.^{[17][18][19][20][21][22]}

Medical significance

PIKfyve mutations affecting one of the two PIKFYVE alleles are found in 8 out of 10 families with Francois-Neetens

Several small molecule PIKfyve inhibitors have shown promise as cancer therapeutics in preclinical studies due to selective toxicity in non-Hodgkin lymphoma B cells [30] or in U-251 glioblastoma cells. ^[31] PIKfyve inhibitors cause cell death also in A-375 melanoma cells, which depend on autophagy for growth and proliferation, due to impaired lysosome homeostasis. ^[32] The potential therapeutic use of PIKfyve inhibitors awaits clinical trials.

Interactions

PIKfyve physically associates with its regulator ArPIKfyve, a protein encoded by the human gene