ArticleThe Journal of biological chemistry2010
ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 47 citations in OpenAlex.
- Lipid alterations in hereditary peripheral neuropathies: common mechanisms in disease heterogeneity?Molecular neurodegeneration · 2026Review
- Homeostatic Influence of Fig4 Outside of the Fab1-Vac14-Fig4 Complex in Saccharomyces cerevisiae.Molecular microbiology · 2025Article
- Phosphoinositides in New Spaces.Cold Spring Harbor perspectives in biology · 2023Review
- Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients.Annals of clinical and translational neurology · 2021Article
- Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J.Molecular neurobiology · 2019Article
- Understanding phosphoinositides: rare, dynamic, and essential membrane phospholipids.The Biochemical journal · 2019Review
- Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination.Annals of neurology · 2018Article
- Charcot Marie Tooth disease type 4J with complex central nervous system features.Annals of clinical and translational neurology · 2018Article
- Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways.International journal of molecular sciences · 2017Review
- FIG4 regulates lysosome membrane homeostasis independent of phosphatase function.Human molecular genetics · 2016Article
- The Protein Complex of Neurodegeneration-related Phosphoinositide Phosphatase Sac3 and ArPIKfyve Binds the Lewy Body-associated Synphilin-1, Preventing Its Aggregation.The Journal of biological chemistry · 2015Article
- The Vac14-interaction network is linked to regulators of the endolysosomal and autophagic pathway.Molecular & cellular proteomics : MCP · 2014Article
- Mouse models of PI(3,5)P2 deficiency with impaired lysosome function.Methods in enzymology · 2014Article
- Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance.BioEssays : news and reviews in molecular, cellular and developmental biology · 2014Review
- The PIKfyve-ArPIKfyve-Sac3 triad in human breast cancer: Functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines.Biochemical and biophysical research communications · 2013Article
- Murine Fig4 is dispensable for muscle development but required for muscle function.Skeletal muscle · 2013Article
- The Sac domain-containing phosphoinositide phosphatases: structure, function, and disease.Frontiers in biology · 2013Article
- Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching.American journal of physiology. Endocrinology and metabolism · 2013Article
- Phosphoinositides: tiny lipids with giant impact on cell regulation.Physiological reviews · 2013Review
- Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.American journal of human genetics · 2013Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The mammalian phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P(2)) phosphatase Sac3 and ArPIKfyve, the associated regulator of the PtdIns3P-5 kinase PIKfyve, form a stable binary complex that associates with PIKfyve in a ternary complex to increase PtdIns(3,5)P(2) production. Whether the ArPIKfyve-Sac3 subcomplex functions outside the PIKfyve context is unknown. Here we show that stable or transient expression of ArPIKfyve(WT) in mammalian cells elevates steady-state protein levels and the PtdIns(3,5)P(2)-hydrolyzing activity of Sac3, whereas knockdown of ArPIKfyve has the opposite effect. These manipulations do not alter the Sac3 mRNA levels, suggesting that ArPIKfyve might control Sac3 protein degradation. Inhibition of protein synthesis in COS cells by cycloheximide reveals remarkably rapid turnover of expressed Sac3(WT) (t((1/2)) = 18.8 min), resulting from a proteasome-dependent clearance as evidenced by the extended Sac3(WT) half-life upon inhibiting proteasome activity. Coexpression of ArPIKfyve(WT), but not the N- or C-terminal halves, prolongs the Sac3(WT) half-life consistent with enhanced Sac3 protein stability through association with full-length ArPIKfyve. We further demonstrate that mutant Sac3, harboring the pathogenic Ile-to-Thr substitution at position 41 found in patients with CMT4J disorder, is similar to Sac3(WT) with regard to PtdIns(3,5)P(2)-hydrolyzing activity, association with ArPIKfyve, or rapid proteasome-dependent clearance. Remarkably, however, neither is the steady-state Sac3(I41T) elevated nor is the Sac3(I41T) half-life extended by coexpressed ArPIKfyve(WT), indicating that unlike with Sac3(WT), ArPIKfyve fails to prevent Sac3(I41T) rapid loss. Together, our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.