ArticleThe Journal of biological chemistry2009
PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis.
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 41 papers.
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Who cites it
41 citing papers in PubMed, 60 citations in OpenAlex.
- In silico discovery and experimental validation of natural derivatives as inhibitor of phosphoinositide Kinase, PIKfyve.Journal of computer-aided molecular design · 2025Article
- A PI(3,5)P2 reporter reveals PIKfyve activity and dynamics on macropinosomes and phagosomes.The Journal of cell biology · 2023Article
- Beyond PI3Ks: targeting phosphoinositide kinases in disease.Nature reviews. Drug discovery · 2023Review
- PIP kinases: A versatile family that demands further therapeutic attention.Advances in biological regulation · 2023Article
- The vacuolar morphology protein VAC14 plays an important role in sexual development in the filamentous ascomycete Sordaria macrospora.Current genetics · 2022Article
- Loss of PIKfyve drives the spongiform degeneration in prion diseases.EMBO molecular medicine · 2021Article
- A Compendium of Information on the Lysosome.Frontiers in cell and developmental biology · 2021Review
- Insights into Lysosomal PI(3,5)PMolecular cell · 2020Article
- Roles for a lipid phosphatase in the activation of its opposing lipid kinase.Molecular biology of the cell · 2020Article
- Using Phosphatidylinositol Phosphorylation as Markers for Hyperglycemic Related Breast Cancer.International journal of molecular sciences · 2020Article
- Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J.Molecular neurobiology · 2019Article
- Biogenesis of lysosome-related organelles complex-1 (BORC) regulates late endosomal/lysosomal size through PIKfyve-dependent phosphatidylinositol-3,5-bisphosphate.Traffic (Copenhagen, Denmark) · 2019Article
- The PIKfyve complex regulates the early melanosome homeostasis required for physiological amyloid formation.Journal of cell science · 2019Article
- Diverse Physiological Functions of FAB1 and Phosphatidylinositol 3,5-Bisphosphate in Plants.Frontiers in plant science · 2019Review
- PIKfyve regulates melanosome biogenesis.PLoS genetics · 2018Article
- Article
- Active vacuolar H+ ATPase and functional cycle of Rab5 are required for the vacuolation defect triggered by PtdIns(3,5)P2 loss under PIKfyve or Vps34 deficiency.American journal of physiology. Cell physiology · 2016Article
- Unexpected severe consequences of Pikfyve deletion by aP2- or Aq-promoter-driven Cre expression for glucose homeostasis and mammary gland development.Physiological reports · 2016Article
- Phosphatidylinositol 3-phosphates-at the interface between cell signalling and membrane traffic.The EMBO journal · 2016Review
- Radiolabeling and Quantification of Cellular Levels of Phosphoinositides by High Performance Liquid Chromatography-coupled Flow Scintillation.Journal of visualized experiments : JoVE · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P(2)) metabolizing enzymes, the kinase PIKfyve and the phosphatase Sac3, constitute a single multiprotein complex organized by the PIKfyve regulator ArPIKfyve and its ability to homodimerize. We previously established that PIKfyve is activated within the triple PIKfyve-ArPIKfyve-Sac3 (PAS) core. These data assign an atypical function for the phosphatase in PtdIns(3,5)P(2) biosynthesis, thus raising the question of whether Sac3 retains its PtdIns(3,5)P(2) hydrolyzing activity within the PAS complex. Herein, we address the issue of Sac3 functionality by a combination of biochemical and morphological assays in triple-transfected COS cells using a battery of truncated or point mutants of the three proteins. We identified the Cpn60_TCP1 domain of PIKfyve as a major determinant for associating the ArPIKfyve-Sac3 subcomplex. Neither Sac3 nor PIKfyve enzymatic activities affected the PAS complex formation or stability. Using the well established formation of aberrant cell vacuoles as a sensitive functional measure of localized PtdIns(3,5)P(2) reduction, we observed a mitigated vacuolar phenotype by kinase-deficient PIKfyve(K1831E) if its ArPIKfyve-Sac3 binding region was deleted, suggesting reduced Sac3 access to, and turnover of PtdIns(3,5)P(2). In contrast, PIKfyve(K1831E), which displays intact ArPIKfyve-Sac3 binding, triggered a more severe vacuolar phenotype if coexpressed with ArPIKfyve(WT)-Sac3(WT) but minimal defects when coexpressed with ArPIKfyve(WT) and phosphatase-deficient Sac3(D488A). These data indicate that Sac3 assembled in the PAS regulatory core complex is an active PtdIns(3,5)P(2) phosphatase. Based on these and other data, presented herein, we propose a model of domain interactions within the PAS core and their role in regulating the enzymatic activities.
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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.