Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis
Summary: Protein kinase B (AKT) is essential for cell survival, proliferation, and migration and has been associated with several diseases. Here, we demonstrate that inositol polyphosphate multikinase (IPMK’s) lipid kinase property drives AKT activation via increasing membrane localization and activ...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223007009 |
| _version_ | 1797827782640664576 |
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| author | Luke Reilly Evan R. Semenza George Koshkaryan Subrata Mishra Sujan Chatterjee Efrat Abramson Pamela Mishra Yoshitasu Sei Stephen A. Wank Mark Donowitz Solomon H. Snyder Prasun Guha |
| author_facet | Luke Reilly Evan R. Semenza George Koshkaryan Subrata Mishra Sujan Chatterjee Efrat Abramson Pamela Mishra Yoshitasu Sei Stephen A. Wank Mark Donowitz Solomon H. Snyder Prasun Guha |
| author_sort | Luke Reilly |
| collection | DOAJ |
| description | Summary: Protein kinase B (AKT) is essential for cell survival, proliferation, and migration and has been associated with several diseases. Here, we demonstrate that inositol polyphosphate multikinase (IPMK’s) lipid kinase property drives AKT activation via increasing membrane localization and activation of PDK1 (3-Phosphoinositide-dependent kinase 1), largely independent of class I PI3k (cPI3K). Deletion of IPMK impairs cell migration, which is partially associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent myosin light chain (MLC) phosphorylation. IPMK is highly expressed in intestinal epithelial cells (IEC). Deleting IPMK in IEC reduced AKT phosphorylation and diminished the number of Paneth cells. Ablation of IPMK impaired IEC regeneration both basally and after chemotherapy-induced damage, suggesting a broad role for IPMK in activating AKT and intestinal tissue regeneration. In conclusion, the PI3k activity of IPMK is necessary for PDK1-mediated AKT activation and intestinal homeostasis. |
| first_indexed | 2024-04-09T12:53:52Z |
| format | Article |
| id | doaj.art-85571b9385264238a49f9bb930e9f354 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-09T12:53:52Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-85571b9385264238a49f9bb930e9f3542023-05-14T04:29:22ZengElsevieriScience2589-00422023-05-01265106623Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasisLuke Reilly0Evan R. Semenza1George Koshkaryan2Subrata Mishra3Sujan Chatterjee4Efrat Abramson5Pamela Mishra6Yoshitasu Sei7Stephen A. Wank8Mark Donowitz9Solomon H. Snyder10Prasun Guha11The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USANevada Institute of Personalized Medicine (NIPM), University of Nevada, Las Vegas, NV 89154, USADepartment of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Reference Standard Laboratory, United States Pharmacopeial Convention, Rockville, MD 20852, USANevada Institute of Personalized Medicine (NIPM), University of Nevada, Las Vegas, NV 89154, USADepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USADigestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USADigestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USADepartment of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USAThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding authorThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Nevada Institute of Personalized Medicine (NIPM), University of Nevada, Las Vegas, NV 89154, USA; School of Life Sciences, University of Nevada, Las Vegas, NV 89154, USA; Corresponding authorSummary: Protein kinase B (AKT) is essential for cell survival, proliferation, and migration and has been associated with several diseases. Here, we demonstrate that inositol polyphosphate multikinase (IPMK’s) lipid kinase property drives AKT activation via increasing membrane localization and activation of PDK1 (3-Phosphoinositide-dependent kinase 1), largely independent of class I PI3k (cPI3K). Deletion of IPMK impairs cell migration, which is partially associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent myosin light chain (MLC) phosphorylation. IPMK is highly expressed in intestinal epithelial cells (IEC). Deleting IPMK in IEC reduced AKT phosphorylation and diminished the number of Paneth cells. Ablation of IPMK impaired IEC regeneration both basally and after chemotherapy-induced damage, suggesting a broad role for IPMK in activating AKT and intestinal tissue regeneration. In conclusion, the PI3k activity of IPMK is necessary for PDK1-mediated AKT activation and intestinal homeostasis.http://www.sciencedirect.com/science/article/pii/S2589004223007009GastroenterologyMolecular biologyCell biology |
| spellingShingle | Luke Reilly Evan R. Semenza George Koshkaryan Subrata Mishra Sujan Chatterjee Efrat Abramson Pamela Mishra Yoshitasu Sei Stephen A. Wank Mark Donowitz Solomon H. Snyder Prasun Guha Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis iScience Gastroenterology Molecular biology Cell biology |
| title | Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis |
| title_full | Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis |
| title_fullStr | Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis |
| title_full_unstemmed | Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis |
| title_short | Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis |
| title_sort | loss of pi3k activity of inositol polyphosphate multikinase impairs pdk1 mediated akt activation cell migration and intestinal homeostasis |
| topic | Gastroenterology Molecular biology Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223007009 |
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