PIKFYVE
Description
The PIKFYVE (phosphoinositide kinase, FYVE-type zinc finger containing) is a protein-coding gene located on chromosome 2.
PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene. 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). 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. By directly binding membrane PtdIns(3)P, the FYVE finger domain of PIKfyve is essential in localizing the protein to the cytosolic leaflet of endosomes. 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. Thus, via PtdIns(3,5)P2 production, PIKfyve participates in several aspects of vesicular dynamics, 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. PIKfyve mutations affecting one of the two PIKFYVE alleles are found in 8 out of 10 families with Francois-Neetens corneal fleck dystrophy. Disruption of both PIKFYVE alleles in the mouse is lethal at the stage of pre-implantation embryo.
PIKFYVE is a dual specificity kinase involved in numerous essential cellular processes, including maintaining endomembrane homeostasis, regulating the endocytic-vacuolar pathway, lysosomal trafficking, nuclear transport, and mediating stress- or hormone-induced signaling and cell cycle progression. It is a key component of the PI(3,5)P2 regulatory complex, which controls both the synthesis and breakdown of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). PIKFYVE is the sole enzyme responsible for phosphorylating phosphatidylinositol 3-phosphate on the fifth hydroxyl of the myo-inositol ring, generating PtdIns(3,5)P2. It also catalyzes the phosphorylation of phosphatidylinositol on the fifth hydroxyl of the myo-inositol ring, producing phosphatidylinositol 5-phosphate (PtdIns(5)P). PIKFYVE possesses serine-protein kinase activity, enabling it to autophosphorylate and transphosphorylate. Autophosphorylation inhibits its own phosphatidylinositol 3-phosphate 5-kinase activity, stimulates FIG4 lipid phosphatase activity, and downregulates lipid product formation. PIKFYVE is crucial for endosome functions such as fission and fusion during endosomal cargo transport. It is required for the maturation of early endosomes into late endosomes, phagosomes, and lysosomes. PIKFYVE regulates vacuole maturation and nutrient recovery after the engulfment of macromolecules, initiating the redistribution of accumulated lysosomal contents back into the endosome network. It is a critical regulator of the morphology, degradative activity, and protein turnover of the endolysosomal system in macrophages and platelets. In neutrophils, PIKFYVE is essential for chemotaxis, ROS generation, and phagosome fusion with lysosomes. It plays a key role in antigen processing and presentation by major histocompatibility complex class II (MHC class II) mediated by CTSS. PIKFYVE regulates melanosome biogenesis by controlling the delivery of proteins from the endosomal compartment to the melanosome. It is essential for systemic glucose homeostasis, mediating insulin-induced signals for endosome/actin remodeling during GLUT4 translocation and glucose uptake activation. PIKFYVE supports microtubule-based endosome-to-trans-Golgi network cargo transport through association with SPAG9 and RABEPK. It mediates EGFR trafficking to the nucleus. PIKFYVE is a component of the PI(3,5)P2 regulatory complex/PAS complex, which also includes FIG4 and VAC14. VAC14 nucleates the assembly of the complex, acting as a scaffold by pentamerizing into a star-shaped structure that can bind a single copy each of PIKFYVE and FIG4, coordinating their activities. PIKFYVE interacts with RABEPK via its chaperonin-like domain, recruiting RABEPK to the endosomal membrane. It also interacts with SPAG9 and EGFR.
PIKFYVE is also known as CFD, FAB1, HEL37, PIP5K, PIP5K3, ZFYVE29.
