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. 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. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

PIKFYVE

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 (PtdIns5P) (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).
(Microbial infection) Required for cell entry of coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus EMC (HCoV-EMC) by endocytosis.

1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate metabolic processISS:UniProtKB
Antigen processing and presentation of exogenous peptide antigen via MHC class IIManual Assertion Based On ExperimentIDA:UniProtKB
Intracellular signal transductionIEA:Ensembl
Melanosome organizationManual Assertion Based On ExperimentIDA:UniProtKB
Myelin assemblyIEA:Ensembl
Neutrophil chemotaxisManual Assertion Based On ExperimentIDA:UniProtKB
Peptidyl-serine autophosphorylationISS:UniProtKB
Phagosome maturationManual Assertion Based On ExperimentIDA:UniProtKB
Phagosome-lysosome fusionManual Assertion Based On ExperimentIDA:UniProtKB
Phosphatidylinositol 5-phosphate metabolic processISS:UniProtKB
Phosphatidylinositol biosynthetic processTAS:Reactome
Protein localization to nucleusManual Assertion Based On ExperimentIMP:UniProtKB
Protein targeting to membraneISS:UniProtKB
Receptor-mediated endocytosis of virus by host cellManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of autophagosome assemblyManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Regulation of reactive oxygen species biosynthetic processManual Assertion Based On ExperimentIDA:UniProtKB
Retrograde transport, endosome to GolgiManual Assertion Based On ExperimentIMP:UniProtKB

Endosome membrane
Early endosome membrane
Cytoplasmic vesicle, phagosome membrane
Late endosome membrane
Mainly associated with membranes of the late endocytic pathway.

Corneal dystrophy, fleck (CFD):
A form of stromal corneal dystrophy characterized by numerous small white flecks scattered in all levels of the stroma, with configurations varying from semicircular to wreath-like, curvilinear, or punctate. Although CFD may occasionally cause mild photophobia, patients are typically asymptomatic and have normal vision.

Autophosphorylates which inhibits its own phosphatidylinositol 3-phosphate 5-kinase activity, stimulates FIG4 lipid phosphatase activity and down-regulates lipid product formation (PubMed:33098764).
Dephosphorylated by FIG4 in the PI(3,5)P2 regulatory complex, at Ser-48, Ser-1669 and Ser-2053 (PubMed:33098764).
Phosphorylated in response to insulin at Ser-318 in a protein kinase B (PKB)-dependent manner (PubMed:20513353).