GSK3β Serine 389 Phosphorylation Modulates Cardiomyocyte Hypertrophy and Ischemic Injury.

Laura Vainio,Päivi Lakkisto,Sini M Kinnunen,Juhani Junttila,Saija Taponen,Eveliina Halmetoja,Risto Kerkelä,Johanna Ulvila,Tarja Alakoski,Johanna Magga,Zoltan Szabo

doi:10.3390/ijms222413586

Abstract

Prior studies show that glycogen synthase kinase 3β (GSK3β) contributes to cardiac ischemic injury and cardiac hypertrophy. GSK3β is constitutionally active and phosphorylation of GSK3β at serine 9 (S9) inactivates the kinase and promotes cellular growth. GSK3β is also phosphorylated at serine 389 (S389), but the significance of this phosphorylation in the heart is not known. We analyzed GSK3β S389 phosphorylation in diseased hearts and utilized overexpression of GSK3β carrying ser→ala mutations at S9 (S9A) and S389 (S389A) to study the biological function of constitutively active GSK3β in primary cardiomyocytes. We found that phosphorylation of GSK3β at S389 was increased in left ventricular samples from patients with dilated cardiomyopathy and ischemic cardiomyopathy, and in hearts of mice subjected to thoracic aortic constriction. Overexpression of either GSK3β S9A or S389A reduced the viability of cardiomyocytes subjected to hypoxia–reoxygenation. Overexpression of double GSK3β mutant (S9A/S389A) further reduced cardiomyocyte viability. Determination of protein synthesis showed that overexpression of GSK3β S389A or GSK3β S9A/S389A increased both basal and agonist-induced cardiomyocyte growth. Mechanistically, GSK3β S389A mutation was associated with activation of mTOR complex 1 signaling. In conclusion, our data suggest that phosphorylation of GSK3β at S389 enhances cardiomyocyte survival and protects from cardiomyocyte hypertrophy.

Highlights

This article is an open access articleCardiovascular diseases are the leading cause of morbidity and mortality in the world [1,2]
We found that phosphorylation of Glycogen synthase kinase3β (GSK3β) at serine 389 (S389) was increased both in dilated and ischemic cardiomyopathy hearts (Figure 1A)
S389 regulates and mTOR Complex 1 (mTORC1) phosphorylation of GSK3β at S389 is important for the survival of lymphocytes during double-strand break response [12]

Summary

Introduction

This article is an open access articleCardiovascular diseases are the leading cause of morbidity and mortality in the world [1,2]. Glycogen synthase kinase3β (GSK3β), which is a constitutively active serine/threonine protein kinase found in. GSK3β is active in unstimulated cells, where it phosphorylates and inhibits growth stimulating substrates. There are more than 40 substrates for GSK3 and an additional 500 other potential candidates have been identified [8,9]. GSK3 is regulated through phosphorylation, through complex formation and intracellular localization [10]. Phosphorylation of GSK3β at serine 9 (S9) inactivates the kinase and has been shown to regulate hypertrophic cardiomyocyte growth and viability [7]. The biological function of other GSK3β phosphorylation sites in cardiomyocytes is not well understood. In 2008, Thornton et al reported a complementary phosphorylation site of GSK3β, serine 389

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