ArticleThe Journal of biological chemistry2009
Sac3 is an insulin-regulated phosphatidylinositol 3,5-bisphosphate phosphatase: gain in insulin responsiveness through Sac3 down-regulation in adipocytes.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 41 citations in OpenAlex.
- The vacuolar morphology protein VAC14 plays an important role in sexual development in the filamentous ascomycete Sordaria macrospora.Current genetics · 2022Article
- Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J.Molecular neurobiology · 2019Article
- Comparative Transcriptomics Reveal Key Sheep (Ovis aries) Hypothalamus LncRNAs that Affect Reproduction.Animals : an open access journal from MDPI · 2019Article
- Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination.Annals of neurology · 2018Article
- PI5P and PI(3,5)PCell structure and function · 2017Review
- 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
- Phosphoinositides: Key modulators of energy metabolism.Biochimica et biophysica acta · 2015Review
- Class III PI 3-kinase is the main source of PtdIns3P substrate and membrane recruitment signal for PIKfyve constitutive function in podocyte endomembrane homeostasis.Biochimica et biophysica acta · 2015Article
- Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Phosphoinositides: tiny lipids with giant impact on cell regulation.Physiological reviews · 2013Review
- 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
- AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve.Science signaling · 2013Article
- Functional dissociation between PIKfyve-synthesized PtdIns5P and PtdIns(3,5)P2 by means of the PIKfyve inhibitor YM201636.American journal of physiology. Cell physiology · 2012Article
- Pairing phosphoinositides with calcium ions in endolysosomal dynamics: phosphoinositides control the direction and specificity of membrane trafficking by regulating the activity of calcium channels in the endolysosomes.BioEssays : news and reviews in molecular, cellular and developmental biology · 2011Review
- The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice.The Journal of biological chemistry · 2011Article
- ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder.The Journal of biological chemistry · 2010Article
- PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis.The Journal of biological chemistry · 2009Article
- Arabidopsis FAB1/PIKfyve proteins are essential for development of viable pollen.Plant physiology · 2009Article
- Fig4 deficiency: a newly emerged lysosomal storage disorder?Progress in neurobiologyReview
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Insulin-regulated stimulation of glucose entry and mobilization of fat/muscle-specific glucose transporter GLUT4 onto the cell surface require the phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P(2)) pathway for optimal performance. The reduced insulin responsiveness observed under ablation of the PtdIns(3,5)P(2)-synthesizing PIKfyve and its associated activator ArPIKfyve in 3T3L1 adipocytes suggests that dysfunction of the PtdIns(3,5)P(2)-specific phosphatase Sac3 may yield the opposite effect. Paradoxically, as uncovered recently, in addition to turnover Sac3 also supports PtdIns(3,5)P(2) biosynthesis by allowing optimal PIKfyve-ArPIKfyve association. These opposing inputs raise the key question as to whether reduced Sac3 protein levels and/or hydrolyzing activity will produce gain in insulin responsiveness. Here we report that small interfering RNA-mediated knockdown of endogenous Sac3 by approximately 60%, which resulted in a slight but significant elevation of PtdIns(3,5)P(2) in 3T3L1 adipocytes, increased GLUT4 translocation and glucose entry in response to insulin. In contrast, ectopic expression of Sac3(WT), but not phosphatase-deficient Sac3(D488A), reduced GLUT4 surface abundance in the presence of insulin. Endogenous Sac3 physically assembled with PIKfyve and ArPIKfyve in both membrane and soluble fractions of 3T3L1 adipocytes, but this remained insulin-insensitive. Importantly, acute insulin markedly reduced the in vitro C8-PtdIns(3,5)P(2) hydrolyzing activity of Sac3. The insulin-sensitive Sac3 pool likely controls a discrete PtdIns(3,5)P(2) subfraction as the high pressure liquid chromatography-measurable insulin-dependent elevation in total [(3)H]inositol-PtdIns(3,5)P(2) was minor. Together, our data identify Sac3 as an insulin-sensitive phosphatase whose down-regulation increases insulin responsiveness, thus implicating Sac3 as a novel drug target in insulin resistance.
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Registered trials
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.