Targeting Protein Kinases to Protect Beta-Cell Function and Survival in Diabetes

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jun 27

PMID 38928130

Authors

Stephane Dalle

Affiliations

Soon will be listed here.

Abstract

The prevalence of diabetes is increasing worldwide. Massive death of pancreatic beta-cells causes type 1 diabetes. Progressive loss of beta-cell function and mass characterizes type 2 diabetes. To date, none of the available antidiabetic drugs promotes the maintenance of a functional mass of endogenous beta-cells, revealing an unmet medical need. Dysfunction and apoptotic death of beta-cells occur, in particular, through the activation of intracellular protein kinases. In recent years, protein kinases have become highly studied targets of the pharmaceutical industry for drug development. A number of drugs that inhibit protein kinases have been approved for the treatment of cancers. The question of whether safe drugs that inhibit protein kinase activity can be developed and used to protect the function and survival of beta-cells in diabetes is still unresolved. This review presents arguments suggesting that several protein kinases in beta-cells may represent targets of interest for the development of drugs to treat diabetes.

References

Clark A, Urano F . Endoplasmic reticulum stress in beta cells and autoimmune diabetes. Curr Opin Immunol. 2016; 43:60-66. PMC: 5125892. DOI: 10.1016/j.coi.2016.09.006. View

Hawley S, Davison M, Woods A, DAVIES S, Beri R, Carling D . Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996; 271(44):27879-87. DOI: 10.1074/jbc.271.44.27879. View

Remedi M, Nichols C . Glucokinase Inhibition: A Novel Treatment for Diabetes?. Diabetes. 2023; 72(2):170-174. PMC: 9871191. DOI: 10.2337/db22-0731. View

Skurat A, Dietrich A . Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases. J Biol Chem. 2003; 279(4):2490-8. DOI: 10.1074/jbc.M301769200. View

Buljan M, Ciuffa R, van Drogen A, Vichalkovski A, Mehnert M, Rosenberger G . Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Mol Cell. 2020; 79(3):504-520.e9. PMC: 7427327. DOI: 10.1016/j.molcel.2020.07.001. View

Gantke T, Sriskantharajah S, Sadowski M, Ley S . IκB kinase regulation of the TPL-2/ERK MAPK pathway. Immunol Rev. 2012; 246(1):168-82. DOI: 10.1111/j.1600-065X.2012.01104.x. View

Litovchick L, Florens L, Swanson S, Washburn M, DeCaprio J . DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev. 2011; 25(8):801-13. PMC: 3078706. DOI: 10.1101/gad.2034211. View

Omori K, Nakamura A, Miyoshi H, Yamauchi Y, Kawata S, Takahashi K . Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing β-Cell Mass in Mice. Diabetes. 2021; 70(4):917-931. DOI: 10.2337/db20-0881. View

Rohm T, Meier D, Olefsky J, Donath M . Inflammation in obesity, diabetes, and related disorders. Immunity. 2022; 55(1):31-55. PMC: 8773457. DOI: 10.1016/j.immuni.2021.12.013. View

10.

Kefalas G, Larose L . PERK leads a hub dictating pancreatic β cell homoeostasis. Biol Cell. 2017; 110(2):27-32. DOI: 10.1111/boc.201700059. View

11.

da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule S, Rutter G . Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J. 2003; 371(Pt 3):761-74. PMC: 1223356. DOI: 10.1042/BJ20021812. View

12.

Atkinson M, Eisenbarth G, Michels A . Type 1 diabetes. Lancet. 2013; 383(9911):69-82. PMC: 4380133. DOI: 10.1016/S0140-6736(13)60591-7. View

13.

Ferrari S, Fallahi P, Elia G, Ragusa F, Ruffilli I, Patrizio A . Autoimmune Endocrine Dysfunctions Associated with Cancer Immunotherapies. Int J Mol Sci. 2019; 20(10). PMC: 6566424. DOI: 10.3390/ijms20102560. View

14.

Salvi M, Sarno S, Cesaro L, Nakamura H, Pinna L . Extraordinary pleiotropy of protein kinase CK2 revealed by weblogo phosphoproteome analysis. Biochim Biophys Acta. 2009; 1793(5):847-59. DOI: 10.1016/j.bbamcr.2009.01.013. View

15.

Servas C, Kiehlmeier S, Hach J, Gross R, Gotz C, Montenarh M . The mammalian STE20-like kinase 1 (MST1) is a substrate for the apoptosis inhibiting protein kinase CK2. Cell Signal. 2017; 36:163-175. DOI: 10.1016/j.cellsig.2017.05.005. View

16.

Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P . Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells. Mol Metab. 2017; 6(9):1024-1039. PMC: 5605732. DOI: 10.1016/j.molmet.2017.06.001. View

17.

Hagerkvist R, Sandler S, Mokhtari D, Welsh N . Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning. FASEB J. 2006; 21(2):618-28. DOI: 10.1096/fj.06-6910com. View

18.

Meng R, Gotz C, Montenarh M . The role of protein kinase CK2 in the regulation of the insulin production of pancreatic islets. Biochem Biophys Res Commun. 2010; 401(2):203-6. DOI: 10.1016/j.bbrc.2010.09.028. View

19.

Burke J, Pattoli M, Gregor K, Brassil P, MacMaster J, McIntyre K . BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J Biol Chem. 2002; 278(3):1450-6. DOI: 10.1074/jbc.M209677200. View

20.

Manley P, Cowan-Jacob S, Buchdunger E, Fabbro D, Fendrich G, Furet P . Imatinib: a selective tyrosine kinase inhibitor. Eur J Cancer. 2003; 38 Suppl 5:S19-27. DOI: 10.1016/s0959-8049(02)80599-8. View