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| Aliases | FIG4 , ALS11, CMT4J, KIAA0274, SAC3, YVS, dJ249I4.1, BTOP, Fig4, FIG4 phosphoinositide 5-phosphatase | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 609390 MGI: 2143585 HomoloGene: 6713 GeneCards: FIG4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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. [5] Fig4 is an abbreviation for Factor-Induced Gene. [6]
Sac3 protein belongs to a family of human phosphoinositide phosphatases containing a Sac1-homology domain. The Sac1 phosphatase domain encompasses approximately 400 amino acids and consists of seven conserved motifs. It harbors the signature CX5R (T/S) catalytic sequence also found in other lipid and protein tyrosine phosphatases. [7] The founding protein, containing this evolutionarily-conserved domain, has been the first gene product isolated in a screen for Suppressors of yeast ACtin mutations and therefore named Sac1. [8] There are 5 human genes containing a Sac1 domain. Three of these genes (gene symbols SACM1L, INPP5F and FIG4), harbor a single Sac1 domain. [9] In the other two genes, synaptojanin 1 and 2, the Sac1 domain coexists with another phosphoinositide phosphatase domain, with both domains supporting phosphate hydrolysis. [10] [11] [12] In humans, the FIG4 gene localizes on chromosome 6 and encodes a Sac3 protein of 907 amino acids. [13] Sac3 is characterized as a widespread 97-kDa protein that, in in vitro assays, displays phosphatase activity towards a range of 5’-phosphorylated phosphoinositides. [14] [15] Sac3 forms a hetero-oligomer with ArPIKfyve (gene symbol, VAC14) and this binary complex associates with the phosphoinositide kinase PIKFYVE in a ternary PAS complex (from the first letters of PIKfyve-ArPIKfyve-Sac3), which is required to maintain proper endosomal membrane dynamics. [16] [17] This unique physical association of two enzymes with opposing functions leads to activation of the phosphoinositide kinase PIKfyve and increases of PIKfyve-catalized PtdIns(3,5)P2 and PtdIns5P production. Sac3 is active as a phosphatase in the triple complex and is responsible for turning over PtdIns(3,5)P2 to PtdIns3P. [16] [17] The PAS complex function is critical for life, because the knockout of each of the 3 genes encoding the PIKfyve, ArPIKfyve or Sac3 protein causes early embryonic, [18] perinatal, [19] or early juvenile lethality [20] in mice. Ectopically expressed Sac3 protein has a very short half-life of only ~18 min due to fast degradation in the proteasome. Co-expression of ArPIKfyve markedly prolongs Sac3 half-life, whereas siRNA-mediated ArPIKfyve knockdown profoundly reduces Sac3 levels. Thus, the Sac3 cellular levels are critically dependent on Sac3 physical interaction with ArPIKfyve. [16] [21] The C-terminal part of Sac3 is essential for this interaction. [17] Insulin treatment of 3T3L1 adipocytes inhibits the Sac3 phosphatase activity as measured in vitro. Small interfering RNA-mediated knockdown of endogenous Sac3 by ~60%, resulting in a slight but significant elevation of PtdIns(3,5)P2 in 3T3L1 adipocytes, increases GLUT4 translocation and glucose uptake in response to insulin. In contrast, ectopic expression of Sac3, but not that of a phosphatase-deficient point-mutant, decreases GLUT4 plasma membrane abundance in response to insulin. Thus, Sac3 is an insulin-sensitive lipid phosphatase whose down-regulation improves insulin responsiveness. [22]
Mutations in the FIG4 gene cause a rare autosomal recessive Charcot-Marie-Tooth peripheral neuropathy type 4J (CMT4J). [20] Most CMT4J patients (15 out of the reported 16) are compound heterozygotes, i.e., the one FIG4 allele is null whereas the other encodes a mutant protein with threonine for isoleucine substitution at position 41. [23] The Sac3I41T point mutation abrogates the protective action of ArPIKfyve on Sac3 half-life. As a result mutant Sac3 is rapidly degraded in the proteasome. [21] Consequently, the Sac3I41T protein level in patient fibroblasts is from very low to undetectable. [24] [25] Clinically, the onset and severity of CMT4J symptoms vary markedly, suggesting an important role of genetic background in the individual course of disease. [25] In two siblings, with severe peripheral motor deficits and moderate sensory symptoms, the disease had relatively little impact on the central nervous system. [26] Phosphoinositide profiling in fibroblasts derived from the largest CMT4J cohort reported in USA thus far reveals decreased steady-state levels of both PtdIns(3,5)P2 and PtdIns5P. This unexpected direction of the changes is a result of impaired activation of the PIKFYVE kinase under the condition of Sac3 protein deficiency and a failure of the PAS complex assembly. [27] The reduction in PtdIns(3,5)P2 and PtdIns5P levels is reportedly unrelated to gender or the disease onset, suggesting that the pathological decline in levels of the two lipids might precede the disease symptoms. [27] FIG4 mutations are also found (without proven causation) in patients with amyotrophic lateral sclerosis (ALS) [28] as well as in other spectrum of phenotypes such as Yunis-Varon syndrome, cortical malformation with seizures and psychiatric co-morbidities, and cerebral hypomyelination.
Spontaneous FIG4 knockout leads to mutant mice with smaller size, selectively reduced PtdIns(3,5)P2 levels in isolated fibroblasts, diluted pigmentation, central and peripheral neurodegeneration, hydrocephalus, abnormal tremor and gait, and eventually juvenile lethality, hence the name pale tremor mouse (plt). [20] [24] Neuronal autophagy has been suggested as an important consequence of the knockout, [29] however, its primary relevance is disputed. [30] The plt mice show distinct morphological defects in motor and central neurons on the one hand, and sensory neurons - on the other. [30] Transgenic mice with one spontaneously null allele and another encoding several copies of mouse Sac3I41T mutant (i.e., the genotypic equivalent of human CMT4J), are dose-dependently rescued from the lethality, neurodegeneration, and brain apoptosis observed in the plt mice. However, the hydrocephalus and diluted pigmentation seen in plt mice are not corrected. [24]
Genes encoding orthologs of human Sac3 are found in all eukaryotes. The most studied is the S. cerevisiae gene, discovered in a screen for yeast pheromone (Factor)-Induced Genes, hence the name Fig, with the number 4 reflecting the serendipity of isolation. [31] Yeast Fig4p is a specific PtdIns(3,5)P2 5’-phosphatase, which physically interacts with Vac14p (the ortholog of human ArPIKfyve), [32] and the PtdIns(3,5)P2-producing enzyme Fab1p (the ortholog of PIKfyve). [33] The yeast Fab1p-Vac14p-Fig4p complex also involves Vac7p and potentially Atg18p. [34] Deletion of Fig4p in budding yeast has relatively little effect on growth, basal PtdIns(3,5)P2 levels and the vacuolar size in comparison with the deletions of Vac14p or Fab1p. [35] In brief, in evolution Sac3/Fig4 retained the Sac1 domain, phosphoinositide phosphatase activity, and the protein interactions from yeast. In mice, the protein is essential in early postnatal development. In humans, its I41T point mutation in combination with a null allele causes a neurodegenerative disorder.
Phosphatidylinositol consists of a family of lipids made of a phosphate group, two fatty acid chains, and one inositol molecule. They represent a class of the phosphatidylglycerides. Typically phosphatidylinositols form a minor component on the cytosolic side of eukaryotic cell membranes. The phosphate group gives the molecules a negative charge at physiological pH.
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 (PtdIns3P) 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.
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.
Lewis C. Cantley is an American cell biologist and biochemist who has made significant advances to the understanding of cancer metabolism. Among his most notable contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer and diabetes mellitus. He is currently Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. He was formerly a professor in the Departments of Systems Biology and Medicine at Harvard Medical School, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center, in Boston, Massachusetts. In 2016, he was elected Chairman of the Board for the Hope Funds for Cancer Research.
SacI homology domain is most notably found at the amino terminal of the inositol 5'-phosphatase synaptojanin. Synaptic vesicles are recycled with remarkable speed and precision in nerve terminals. A major recycling pathway involves clathrin-mediated endocytosis at endocytic zones located around sites of release. Different 'accessory' proteins linked to this pathway have been shown to alter the shape and composition of lipid membranes, to modify membrane-coat protein interactions, and to influence actin polymerization. These include the GTPase dynamin, the lysophosphatidic acid acyl transferase endophilin, and the phosphoinositide phosphatase synaptojanin.
Protein VAC14 homolog, also known as ArPIKfyve, is a protein that in humans is encoded by the VAC14 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.
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.
