Evidence map›Paper›PMID 38735134›Full record

ArticleBiochemical and biophysical research communications2024

A high dose KRP203 induces cytoplasmic vacuoles associated with altered phosphoinositide segregation and endosome expansion.

Satoshi Kofuji, Kara Wolfe, Kazutaka Sumita, Shun Kageyama, Hirofumi Yoshino, Yoshihisa Hirota, Aki Ogawa-Iio, Hirotaka Kanoh, Mika Sasaki, Kaori Kofuji and 13 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Biochemical and biophysical research communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors.

Satoshi KofujiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
Kara WolfeDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
Kazutaka SumitaDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Endovascular Surgery, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
Shun KageyamaInstitute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0052, Japan.
Hirofumi YoshinoDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
Yoshihisa HirotaDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Minuma-ku, Saitama, 337-8570, Japan.
Aki Ogawa-IioDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Minuma-ku, Saitama, 337-8570, Japan.
Hirotaka KanohInstitute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0052, Japan.
Mika SasakiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
Kaori KofujiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
Mindy I DavisNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Rajan PraganiNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Min ShenNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Matthew B BoxerNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Fubito NakatsuDepartment of Neurochemistry and Molecular Cell Biology, Niigata University School of Medicine and Graduate School of Medical/Dental Sciences, Niigata, Japan.
Kiyomi NigorikawaGraduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Takehiko SasakiDepartment of Biochemical Pathophysiology, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
Koh TakeuchiGraduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.
Toshiya SendaStructural Biology Research Center, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, 305-0801, Japan; Department of Accelerator Science, SOKENDAI, Japan; Faculty of Pure and Applied Sciences, University of Tsukuba, Ibaraki, 305-8572, Japan.
Seong M KimDepartment of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, California, 92697, USA.
Aimee L EdingerDepartment of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, California, 92697, USA.
Anton SimeonovNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Atsuo T SasakiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0052, Japan; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Neurosurgery, Brain Tumor Center at UC Gardner Neuroscience Institute, Cincinnati, OH, 45267, USA; Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, 734-8551, Japan. Electronic address: sasakigtp@gmail.com.

Funding

Univ.of Calif., Irvine Cancer Center Support GrantP30CA062203 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Melanie Funes · 1994 to 2026
$57.9M
Mechanistic role of phosphatidylinositol 5-phosphate 4-kinase beta in GTP-dependent lysosomal acidification for stress-resilient cell growth and metabolismR01GM144426 · NIGMS · UNIVERSITY OF CINCINNATI · PI Atsuo Sasaki · 2023 to 2026
$1.7M
Effects of sphingolipids on nutrient transporter expression and bioenergeticsR01GM089919 · NIGMS · UNIVERSITY OF CALIFORNIA-IRVINE · PI EDINGER, AIMEE L · 2010 to 2014
$1.5M
NCI NIH HHS P30 CA062203NIGMS NIH HHS R01 GM089919NIGMS NIH HHS R01 GM144426
6 · The paper itself

Abstract

In animal cells, vacuoles are absent, but can be induced by diseases and drugs. While phosphoinositides are critical for membrane trafficking, their role in the formation of these vacuoles remains unclear. The immunosuppressive KRP203/Mocravimod, which antagonizes sphingosine-1-phosphate receptors, has been identified as having novel multimodal activity against phosphoinositide kinases. However, the impact of this novel KRP203 activity is unknown. Here, we show that KRP203 disrupts the spatial organization of phosphoinositides and induces extensive vacuolization in tumor cells and immortalized fibroblasts. The KRP203-induced vacuoles are primarily from endosomes, and augmented by inhibition of PIKFYVE and VPS34. Conversely, overexpression of PTEN decreased KRP203-induced vacuole formation. Furthermore, V-ATPase inhibition completely blunted KRP203-induced vacuolization, pointing to a critical requirement of the endosomal maturation process. Importantly, nearly a half of KRP203-induced vacuoles are significantly decorated with PI4P, a phosphoinositide typically enriched at the plasma membrane and Golgi. These results suggest a model that noncanonical spatial reorganization of phosphoinositides by KRP203 alters the endosomal maturation process, leading to vacuolization. Taken together, this study reveals a previously unrecognized bioactivity of KRP203 as a vacuole-inducing agent and its unique mechanism of phosphoinositide modulation, providing a new insight of phosphoinositide regulation into vacuolization-associated diseases and their molecular pathologies.

Indexed as

EndosomesPhosphatidylinositolsPTEN PhosphohydrolaseVacuolesAminopyridinesAnimalsClass III Phosphatidylinositol 3-KinasesCytoplasmHeLa CellsHeterocyclic Compounds, 3-RingHumansMiceMorpholinesPhosphatidylinositol 3-KinasesVacuolar Proton-Translocating ATPases6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamideAminopyridinesClass III Phosphatidylinositol 3-KinasesHeterocyclic Compounds, 3-RingMorpholinesPhosphatidylinositol 3-KinasesPhosphatidylinositolsPIKFYVE protein, humanPTEN PhosphohydrolaseVacuolar Proton-Translocating ATPasesEndosomeKRP203MocravimodPhosphoinositideRABVacuolization

Identifiers

PMID38735134
PMCPMC11416131

What OpenQuestion holds

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Registered trials

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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.