Glycogen Synthase Kinase-3beta Plays a Pro-apoptotic Role in Beta-adrenergic Receptor-stimulated Apoptosis in Adult Rat Ventricular Myocytes: Role of Beta1 Integrins

Overview

Journal J Mol Cell Cardiol

Specialty Cardiology & Vascular Diseases

Date 2007 Feb 13

PMID 17292911

Citations 26

Authors

Bindu Menon

Jennifer N Johnson

Robert S Ross

Mahipal Singh

Krishna Singh

Affiliations

Soon will be listed here.

Abstract

Beta-adrenergic receptor (beta-AR) stimulation induces apoptosis in adult rat ventricular myocytes (ARVM). beta1 integrin signaling plays a protective role in beta-AR-stimulated apoptosis. Glycogen synthase kinase-3beta (GSK-3beta), a multifunctional serine/threonine kinase, negatively regulates cardiac hypertrophy. Here we show that beta-AR stimulation (isoproterenol; 15 min) increases tyr(216) phosphorylation and GSK-3beta activity. Inclusion of LiCl, inhibitor of GSK-3beta, in the reaction mix or expression of catalytically inactive GSK-3beta (KM-GSK) inhibited beta-AR-stimulated GSK-3beta activity. Inhibition of tyrosine kinase using genistein or chelation of intracellular Ca(2+) using BAPTA-AM inhibited beta-AR-stimulated increases in tyr(216) phosphorylation and GSK-3beta activity. Inhibition of GSK-3beta using pharmacological inhibitors or infection with KM-GSK decreased beta-AR-stimulated cytosolic cytochrome C release and apoptosis. Expression of beta1 integrins increased ser(9) phosphorylation and inhibited beta-AR-stimulated increase in GSK-3beta activity. Wortmannin, inhibitor of PI3-kinase, reversed the effects of beta1 integrins on GSK-3beta activity and apoptosis. Purified active matrix metalloproteinase-2 (MMP-2), shown to interfere with beta1 integrin signaling, increased GSK-3beta activity, while inhibition of MMP-2 inhibited beta-AR-stimulated increases in GSK-3beta activity. beta-AR stimulation induced nuclear accumulation of GSK-3beta. beta-AR stimulation (3 h) increased the expression of transcription factor Gadd153 (growth arrest- and DNA damage-inducible gene 153). These data suggest that beta-AR stimulation increases GSK-3beta activity. Activation of GSK-3beta plays a pro-apoptotic role in beta-AR-stimulated apoptosis via the involvement of mitochondrial death pathway. beta1 integrins inactivate GSK-3beta and play an anti-apoptotic role via the involvement of PI3-kinase pathway. The apoptotic effects of GSK-3beta may be mediated, at least in part, via its nuclear localization and induction of pro-apoptotic genes, such as Gadd153.

Citing Articles

Almost 50 Years of Monomeric Extracellular Ubiquitin (eUb).

Mendoza-Salazar I, Fragozo A, Gonzalez-Martinez A, Trejo-Martinez I, Arreola R, Pavon L Pharmaceuticals (Basel). 2024; 17(2).

PMID: 38399400 PMC: 10892293. DOI: 10.3390/ph17020185.

Post-ischemic cardioprotective potential of exogenous ubiquitin in myocardial remodeling late after ischemia/reperfusion injury.

Dalal S, Shook P, Singh M, Singh K Life Sci. 2022; 312:121216.

PMID: 36435225 PMC: 9784153. DOI: 10.1016/j.lfs.2022.121216.

Cardioprotective Potential of Exogenous Ubiquitin.

Dalal S, Shook P, Singh M, Singh K Cardiovasc Drugs Ther. 2020; 35(6):1227-1232.

PMID: 32910339 PMC: 9272944. DOI: 10.1007/s10557-020-07042-5.

Regulatory Dendritic Cells Induced by K313 Display Anti-Inflammatory Properties and Ameliorate Experimental Autoimmune Encephalitis in Mice.

Zhou Y, Leng X, Luo X, Mo C, Zou Q, Liu Y Front Pharmacol. 2020; 10:1579.

PMID: 32063843 PMC: 6997778. DOI: 10.3389/fphar.2019.01579.

Exogenous ubiquitin attenuates hypoxia/reoxygenation-induced cardiac myocyte apoptosis via the involvement of CXCR4 and modulation of mitochondrial homeostasis.

Dalal S, Daniels C, Li Y, Wright G, Singh M, Singh K Biochem Cell Biol. 2020; 98(4):492-501.

PMID: 31967865 PMC: 7416794. DOI: 10.1139/bcb-2019-0339.

References

Hartigan J, Xiong W, JOHNSON G . Glycogen synthase kinase 3beta is tyrosine phosphorylated by PYK2. Biochem Biophys Res Commun. 2001; 284(2):485-9. DOI: 10.1006/bbrc.2001.4986. View

Shiraishi H, Okamoto H, Yoshimura A, Yoshida H . ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci. 2006; 119(Pt 19):3958-66. DOI: 10.1242/jcs.03160. View

Haq S, Choukroun G, Kang Z, Ranu H, Matsui T, Rosenzweig A . Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy. J Cell Biol. 2000; 151(1):117-30. PMC: 2189812. DOI: 10.1083/jcb.151.1.117. View

Li M, Wang X, Meintzer M, Laessig T, Birnbaum M, Heidenreich K . Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol Cell Biol. 2000; 20(24):9356-63. PMC: 102192. DOI: 10.1128/MCB.20.24.9356-9363.2000. View

McCullough K, Martindale J, Klotz L, Aw T, Holbrook N . Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001; 21(4):1249-59. PMC: 99578. DOI: 10.1128/MCB.21.4.1249-1259.2001. View

Morisco C, Seta K, Hardt S, Lee Y, Vatner S, Sadoshima J . Glycogen synthase kinase 3beta regulates GATA4 in cardiac myocytes. J Biol Chem. 2001; 276(30):28586-97. DOI: 10.1074/jbc.M103166200. View

Grimes C, Jope R . The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol. 2001; 65(4):391-426. DOI: 10.1016/s0301-0082(01)00011-9. View

Bijur G, Jope R . Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem. 2001; 276(40):37436-42. PMC: 1973163. DOI: 10.1074/jbc.M105725200. View

Singh K, Xiao L, Remondino A, Sawyer D, Colucci W . Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol. 2001; 189(3):257-65. DOI: 10.1002/jcp.10024. View

10.

Tong H, Imahashi K, Steenbergen C, Murphy E . Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective. Circ Res. 2002; 90(4):377-9. DOI: 10.1161/01.res.0000012567.95445.55. View

11.

Haq S, Michael A, Andreucci M, Bhattacharya K, Dotto P, Walters B . Stabilization of beta-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth. Proc Natl Acad Sci U S A. 2003; 100(8):4610-5. PMC: 153603. DOI: 10.1073/pnas.0835895100. View

12.

Communal C, Singh M, Menon B, Xie Z, Colucci W, Singh K . beta1 integrins expression in adult rat ventricular myocytes and its role in the regulation of beta-adrenergic receptor-stimulated apoptosis. J Cell Biochem. 2003; 89(2):381-8. DOI: 10.1002/jcb.10520. View

13.

Bijur G, Jope R . Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria. Neuroreport. 2003; 14(18):2415-9. DOI: 10.1097/00001756-200312190-00025. View

14.

Conant K, St Hillaire C, Nagase H, Visse R, Gary D, Haughey N . Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt. J Biol Chem. 2003; 279(9):8056-62. DOI: 10.1074/jbc.M307051200. View

15.

Takahashi-Yanaga F, Shiraishi F, Hirata M, Miwa Y, Morimoto S, Sasaguri T . Glycogen synthase kinase-3beta is tyrosine-phosphorylated by MEK1 in human skin fibroblasts. Biochem Biophys Res Commun. 2004; 316(2):411-5. DOI: 10.1016/j.bbrc.2004.02.061. View

16.

Oyadomari S, Mori M . Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2003; 11(4):381-9. DOI: 10.1038/sj.cdd.4401373. View

17.

Hardt S, Tomita H, Katus H, Sadoshima J . Phosphorylation of eukaryotic translation initiation factor 2Bepsilon by glycogen synthase kinase-3beta regulates beta-adrenergic cardiac myocyte hypertrophy. Circ Res. 2004; 94(7):926-35. DOI: 10.1161/01.RES.0000124977.59827.80. View

18.

Jope R, Johnson G . The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004; 29(2):95-102. DOI: 10.1016/j.tibs.2003.12.004. View

19.

Michael A, Haq S, Chen X, Hsich E, Cui L, Walters B . Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heart. J Biol Chem. 2004; 279(20):21383-93. DOI: 10.1074/jbc.M401413200. View

20.

Juhaszova M, Zorov D, Kim S, Pepe S, Fu Q, Fishbein K . Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest. 2004; 113(11):1535-49. PMC: 419483. DOI: 10.1172/JCI19906. View