Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis
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
Affiliations
Luke Reilly
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Evan R. Semenza
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
George Koshkaryan
Nevada Institute of Personalized Medicine (NIPM), University of Nevada, Las Vegas, NV 89154, USA
Subrata Mishra
Department 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, USA
Sujan Chatterjee
Nevada Institute of Personalized Medicine (NIPM), University of Nevada, Las Vegas, NV 89154, USA
Efrat Abramson
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Pamela Mishra
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
Yoshitasu Sei
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
Stephen A. Wank
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
Mark Donowitz
Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA
Solomon H. Snyder
The 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 author
Prasun Guha
The 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 author
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.
