PIKFYVE

Phosphorylated derivatives of phosphatidylinositol (PtdIns) regulate cytoskeletal functions, membrane trafficking, and receptor signaling by recruiting protein complexes to cell- and endosomal-membranes. Humans have multiple PtdIns proteins that differ by the degree and position of phosphorylation of the inositol ring. This gene encodes an enzyme (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) that phosphorylates the D-5 position in PtdIns and phosphatidylinositol-3-phosphate (PtdIns3P) to make PtdIns5P and PtdIns(3,5)biphosphate. The D-5 position also can be phosphorylated by type I PtdIns4P-5-kinases (PIP5Ks) that are encoded by distinct genes and preferentially phosphorylate D-4 phosphorylated PtdIns. In contrast, PIKfyve preferentially phosphorylates D-3 phosphorylated PtdIns. In addition to being a lipid kinase, PIKfyve also has protein kinase activity. PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosome carrier vesicles from early endosomes. The protein plays a key role in cell entry of ebola virus and SARS-CoV-2 by endocytosis Mutations in this gene cause corneal fleck dystrophy (CFD); an autosomal dominant disorder characterized by numerous small white flecks present in all layers of the corneal stroma. Histologically, these flecks appear to be keratocytes distended with lipid and mucopolysaccharide filled intracytoplasmic vacuoles. [provided by RefSeq, Jul 2021]
Diseases associated with PIKFYVE include Corneal Dystrophy, Fleck and Corneal Dystrophy. Among its related pathways are PI Metabolism and Metabolism. Gene Ontology (GO) annotations related to this gene include obsolete phosphatidylinositol phosphate kinase activity and phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity. An important paralog of this gene is CCT6A.
Dual specificity kinase implicated in myriad essential cellular processes such as maintenance of endomembrane homeostasis, and endocytic-vacuolar pathway, lysosomal trafficking, nuclear transport, stress- or hormone-induced signaling and cell cycle progression (PubMed:23086417).
The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).
Sole enzyme to catalyze the phosphorylation of phosphatidylinositol 3-phosphate on the fifth hydroxyl of the myo-inositol ring, to form (PtdIns(3,5)P2) (PubMed:17556371).
Also catalyzes the phosphorylation of phosphatidylinositol on the fifth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 5-phosphate (PtdIns(5)P) (PubMed:22621786).
Has serine-protein kinase activity and is able to autophosphorylate and transphosphorylate.
Autophosphorylation inhibits its own phosphatidylinositol 3-phosphate 5-kinase activity, stimulates FIG4 lipid phosphatase activity and down-regulates lipid product formation (PubMed:33098764).
Involved in key endosome operations such as fission and fusion in the course of endosomal cargo transport (PubMed:22621786).
Required for the maturation of early into late endosomes, phagosomes and lysosomes (PubMed:30612035).
Regulates vacuole maturation and nutrient recovery following engulfment of macromolecules, initiates the redistribution of accumulated lysosomal contents back into the endosome network (PubMed:27623384).
Critical regulator of the morphology, degradative activity, and protein turnover of the endolysosomal system in macrophages and platelets (By similarity).
In neutrophils, critical to perform chemotaxis, generate ROS, and undertake phagosome fusion with lysosomes (PubMed:28779020).
Plays a key role in the processing and presentation of antigens by major histocompatibility complex class II (MHC class II) mediated by CTSS (PubMed:30612035).
Regulates melanosome biogenesis by controlling the delivery of proteins from the endosomal compartment to the melanosome (PubMed:29584722).
Essential for systemic glucose homeostasis, mediates insulin-induced signals for endosome/actin remodeling in the course of GLUT4 translocation/glucose uptake activation (By similarity).
Supports microtubule-based endosome-to-trans-Golgi network cargo transport, through association with SPAG9 and RABEPK (By similarity).
Mediates EGFR trafficking to the nucleus (PubMed:17909029).
Inhibited by apilimod and YM201636.
related to S cerevisiae phosphatidylinositol-4-phosphatase-5 kinase (FAB1)
Endosome membrane; Peripheral membrane protein {ECO:0000269 PubMed:11706043, 17556371 | ECO:0000250 UniProtKB:Q9Z1T6}
Early endosome membrane; Peripheral membrane protein {ECO:0000269 PubMed:30612035}
Cytoplasmic vesicle, phagosome membrane; Peripheral membrane protein {ECO:0000269 PubMed:30612035 | ECO:0000305}
Late endosome membrane; Peripheral membrane protein {ECO:0000269 PubMed:11706043 | ECO:0000250 UniProtKB:Q9Z1T6}
Note: Mainly associated with membranes of the late endocytic pathway {ECO:0000269 PubMed:11706043}
Quaternary structure:
Component of the PI(3,5)P2 regulatory complex/PAS complex, at least composed of PIKFYVE, FIG4 and VAC14.
VAC14 nucleates the assembly of the complex and serves as a scaffold by pentamerizing into a star-shaped structure, which can bind a single copy each of PIKFYVE and FIG4 and coordinates their activities (PubMed:17556371, 18950639, 33098764).
Interacts (via chaperonin-like domain) with RABEPK; the interaction recruits RABEPK to the endosomal membrane (PubMed:14530284).
Interacts with SPAG9 (By similarity).
Interacts with EGFR (PubMed:17909029).