| VAC14 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | VAC14 , ArPIKfyve, TAX1BP2, TRX, Vac14, PIKFYVE complex component, VAC14 component of PIKFYVE complex | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 604632; MGI: 2157980; HomoloGene: 6528; GeneCards: VAC14; OMA:VAC14 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Protein VAC14 homolog, also known as ArPIKfyve (Associated Regulator of PIKfyve), is a protein that in humans is encoded by the VAC14 gene. [5] [6] [7]
The content of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) in endosomal membranes changes dynamically with fission and fusion events that generate or absorb intracellular transport vesicles. The ArPIKfyve protein scaffolds a trimolecular complex to tightly regulate the level of PtdIns(3,5)P2. Other components of this complex are the PtdIns(3,5)P2-synthesizing enzyme PIKFYVE and the Sac1-domain-containing PtdIns(3,5)P2 5-phosphatase Sac3, encoded by the human gene FIG4. VAC14 functions as an activator of PIKFYVE. [5] [8] Studies in VAC14 knockout mice indicate that, in addition to increasing the PtdIns(3,5)P2-producing activity of PIKfyve, VAC14 also controls the steady-state levels of another rare phosphoinositide linked to PIKfyve enzyme activity – phosphatidylinositol 5-phosphate. It is seen that VAC14 is scaffold protein that acts in complex with the lipid kinase PIKfyve which works to phosphorylate phosphatidylinositol-3-phosphate, as well as the counteracting phosphatase FIG4, which removes a phosphate group. [9]
In addition to the formation of the ternary complex with PIKfyve and Sac3, ArPIKfyve is engaged in a number of other interactions. ArPIKfyve forms a stable complex with the PtdIns(3,5)P2-specific phosphatase Sac3, thereby protecting Sac3 from rapid degradation in the proteasome. [10] ArPIKfyve forms a homooligomer through its carboxyl terminus. However, the number of monomers in the ArPIKfyve homooligomer, ArPIKfyve-Sac3 heterodimer or PIKfyve-ArPIKfyve-Sac3 heterotrimer is unknown. [11] Human Vac14/ArPIKfyve also interacts with the PDZ (post-synaptic density) domain of neuronal nitric oxide synthase [12] but the functional significance of this interaction is still unclear. ArPIKfyve facilitates insulin-regulated GLUT4 translocation to the cell surface. [13]
VAC14 knock-out mice die at, or shortly after birth and exhibit massive neurodegeneration. Fibroblasts from these mice display ~50% lower levels of PtdIns(3,5)P2 and PtdIns(5)P. [14] A spontaneous mouse VAC14-point mutation (with arginine substitution of leucine156) is associated with reduced life span (up to 3 weeks), body size, enlarged brain ventricles, 50% decrease in PtdIns(3,5)P2 levels, diluted pigmentation, tremor and impaired motor function. [15]
In 2016, a new condition caused by mutations of the gene was discovered and named childhood-onset striatonigral degeneration (OMIM 617054) [16] It is thought that the PIKfyve-VAC14-FIG4 complex plays an important role on the maturation of early endosomes to late endosomes/lysosomes. These organelles play critical roles in vesicular trafficking, which move cargo from donor membrane cells to target membranes within the body. [17]
Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found in eukaryotes, and was found to be a signaling molecule.
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid that resides on the plasma membrane.
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.
Phosphatidylinositol 3-phosphate (PI3P) is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and III phosphoinositide 3-kinases activity on phosphatidylinositol.
Phosphatidylinositol (3,4)-bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways.
Phosphatidylinositol 3,5-bisphosphate is one of the seven phosphoinositides found in eukaryotic cell membranes. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides. They are approximately 3 to 5-fold lower as compared to PtdIns3P and PtdIns5P levels, and more than 100-fold lower than the abundant PtdIns4P and PtdIns(4,5)P2. PtdIns(3,5)P2 was first reported to occur in mouse fibroblasts and budding yeast S. cerevisiae in 1997. In S. cerevisiae PtdIns(3,5)P2 levels increase dramatically during hyperosmotic shock. The response to hyperosmotic challenge is not conserved in most tested mammalian cells except for differentiated 3T3L1 adipocytes.
The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.
Yunis–Varon syndrome (YVS), also called cleidocranial dysplasia with micrognathia or absent thumbs and distal aphalangia, is an extremely rare autosomal recessive multisystem congenital disorder which affects the skeletal system, ectodermal tissue, heart and respiratory system. It was first described by Emilio Yunis and Humberto Váron from the National University of Colombia.
Phospholipase C epsilon 1 (PLCE1) is an enzyme that in humans is encoded by the PLCE1 gene. This gene encodes a phospholipase enzyme (PLCE1) that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Mutations in this gene cause early-onset nephrotic syndrome and have been associated with respiratory chain deficiency with diffuse mesangial sclerosis.
PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene.
Myotubularin-related protein 2 also known as phosphatidylinositol-3,5-bisphosphate 3-phosphatase or phosphatidylinositol-3-phosphate phosphatase is a protein that in humans is encoded by the MTMR2 gene.
Pleckstrin homology domain-containing family A member 1 is a protein that in humans is encoded by the PLEKHA1 gene.
Rab9 effector protein with Kelch motifs also known as p40 is a protein that in humans is encoded by the RABEPK gene.
Myotubularin related protein 14 also known as MTMR14 is a protein which in humans is encoded by the MTMR14 gene.
Phosphatidylinositol 5-phosphate (PtdIns5P) is a phosphoinositide, one of the phosphorylated derivatives of phosphatidylinositol (PtdIns), that are well-established membrane-anchored regulatory molecules. Phosphoinositides participate in signaling events that control cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation and many other cellular functions. Generally, phosphoinositides transduce signals by recruiting specific phosphoinositide-binding proteins to intracellular membranes.
Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the FIG4 gene. Fig4 is an abbreviation for Factor-Induced Gene.
Vacuolar segregation protein 7 is a protein that in yeast is encoded by the VAC7 gene. VAC7 is a component of the PI(3,5)P2 regulatory complex, composed of ATG18, FIG4, FAB1, VAC14 and VAC7.
Phosphatidylinositol-4,5-bisphosphate 4-phosphatase (EC 3.1.3.78, phosphatidylinositol-4,5-bisphosphate 4-phosphatase I, phosphatidylinositol-4,5-bisphosphate 4-phosphatase II, type I PtdIns-4,5-P2 4-Ptase, type II PtdIns-4,5-P2 4-Ptase, IpgD, PtdIns-4,5-P2 4-phosphatase type I, PtdIns-4,5-P2 4-phosphatase type II, type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase, type 1 4-phosphatase) is an enzyme with systematic name 1-phosphatidyl-1D-myo-inositol-4,5-bisphosphate 4-phosphohydrolase. This enzyme catalyses the following chemical reaction
Apilimod (STA-5326) is a drug that was initially identified as an inhibitor of production of the interleukins IL-12 and IL-23, and developed for the oral treatment of autoimmune conditions such as Crohn's disease and rheumatoid arthritis, though clinical trial results were disappointing and development for these applications was not continued.
