Loss of PI3k Activity of Inositol Polyphosphate Multikinase Impairs PDK1-mediated AKT Activation, Cell Migration, and Intestinal Homeostasis

Overview

Journal iScience

Publisher Cell Press

Date 2023 May 22

PMID 37216099

Authors

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

Soon will be listed here.

Abstract

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.

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References

Sarkaria J, Tibbetts R, Busby E, Kennedy A, Hill D, Abraham R . Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res. 1998; 58(19):4375-82. View

Ebner M, Sinkovics B, Szczygiel M, Ribeiro D, Yudushkin I . Localization of mTORC2 activity inside cells. J Cell Biol. 2017; 216(2):343-353. PMC: 5294791. DOI: 10.1083/jcb.201610060. View

Casamayor A, Morrice N, Alessi D . Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J. 1999; 342 ( Pt 2):287-92. PMC: 1220463. View

Kim S, Kim S, Maag D, Maxwell M, Resnick A, Juluri K . Amino acid signaling to mTOR mediated by inositol polyphosphate multikinase. Cell Metab. 2011; 13(2):215-21. PMC: 3042716. DOI: 10.1016/j.cmet.2011.01.007. View

Yokoyama J, Wang Y, Schork A, Thompson W, Karch C, Cruchaga C . Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease. JAMA Neurol. 2016; 73(6):691-7. PMC: 4905783. DOI: 10.1001/jamaneurol.2016.0150. View

Thachil E, Hugot J, Arbeille B, Paris R, Grodet A, Peuchmaur M . Abnormal activation of autophagy-induced crinophagy in Paneth cells from patients with Crohn's disease. Gastroenterology. 2012; 142(5):1097-1099.e4. DOI: 10.1053/j.gastro.2012.01.031. View

Saiardi A, Erdjument-Bromage H, Snowman A, Tempst P, Snyder S . Synthesis of diphosphoinositol pentakisphosphate by a newly identified family of higher inositol polyphosphate kinases. Curr Biol. 1999; 9(22):1323-6. DOI: 10.1016/s0960-9822(00)80055-x. View

Sheng H, Shao J, Townsend Jr C, Evers B . Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut. 2003; 52(10):1472-8. PMC: 1773820. DOI: 10.1136/gut.52.10.1472. View

Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung S . SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006; 127(1):125-37. DOI: 10.1016/j.cell.2006.08.033. View

10.

Cadwell K, Liu J, Brown S, Miyoshi H, Loh J, Lennerz J . A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008; 456(7219):259-63. PMC: 2695978. DOI: 10.1038/nature07416. View

11.

Harnack C, Berger H, Antanaviciute A, Vidal R, Sauer S, Simmons A . R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nat Commun. 2019; 10(1):4368. PMC: 6761174. DOI: 10.1038/s41467-019-12349-5. View

12.

Komander D, Fairservice A, Deak M, Kular G, Prescott A, Downes C . Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates. EMBO J. 2004; 23(20):3918-28. PMC: 524332. DOI: 10.1038/sj.emboj.7600379. View

13.

Pinner S, Sahai E . PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nat Cell Biol. 2008; 10(2):127-37. DOI: 10.1038/ncb1675. View

14.

Guha P, Tyagi R, Chowdhury S, Reilly L, Fu C, Xu R . IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration. Cell Rep. 2019; 26(10):2692-2703.e7. PMC: 6494083. DOI: 10.1016/j.celrep.2019.02.013. View

15.

Tu-Sekine B, Padhi A, Jin S, Kalyan S, Singh K, Apperson M . Inositol polyphosphate multikinase is a metformin target that regulates cell migration. FASEB J. 2019; 33(12):14137-14146. PMC: 6894044. DOI: 10.1096/fj.201900717RR. View

16.

He X, Yin T, Grindley J, Tian Q, Sato T, Tao W . PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet. 2007; 39(2):189-98. PMC: 4681524. DOI: 10.1038/ng1928. View

17.

Sei Y, Zhao X, Forbes J, Szymczak S, Li Q, Trivedi A . A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase. Gastroenterology. 2015; 149(1):67-78. PMC: 4858647. DOI: 10.1053/j.gastro.2015.04.008. View

18.

Resnick A, Snowman A, Kang B, Hurt K, Snyder S, Saiardi A . Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity. Proc Natl Acad Sci U S A. 2005; 102(36):12783-8. PMC: 1200306. DOI: 10.1073/pnas.0506184102. View

19.

Berridge M, Lipp P, Bootman M . The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2001; 1(1):11-21. DOI: 10.1038/35036035. View

20.

Jung I, Anokye-Danso F, Jin S, Ahima R, Kim S . IPMK modulates hepatic glucose production and insulin signaling. J Cell Physiol. 2022; 237(8):3421-3432. DOI: 10.1002/jcp.30827. View