Myocardial AKT: The Omnipresent Nexus

Sussman, Mark A.; Völkers, Mirko; Fischer, Kimberlee M.; Bailey, Brandi; Cottage, Christopher T.; Din, Shabana; Gude, Natalie; Avitabile, Daniele; Álvarez, Roberto Baelo; Sundararaman, Balaji; Quijada, Pearl; Mason, Matt; Konstandin, Mathias; Malhowski, Amy J.; Cheng, Zhaokang; Khan, Mohsin; McGregor, Michael

doi:10.1152/physrev.00024.2010

Cited by 199 publications

(185 citation statements)

References 681 publications

(891 reference statements)

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“…Akt is activated by a wide range of receptor stimuli to regulate diverse functions including glucose metabolism, cellular growth and survival through phosphorylation of many different target molecules at different cellular compartments. [32][33][34][35][36] One of the most established downstream effectors of Akt is the mammalian (mechanistic) target of rapamycin (mTOR), a serine/threonine kinase. mTOR forms two distinct functional complexes termed mTOR complex 1 and 2 (mTORC1 and mTORC2).…”

Section: Hexokinase II In Metabolismmentioning

confidence: 99%

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Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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Section: Hexokinase II In Metabolismmentioning

confidence: 99%

“…[32][33][34][35][36] Earlier studies found that expression of active Akt increases mitochondrial HK activity and the antiapoptotic effect of Akt required mitoHK. 118 The aforementioned inhibitory effect of mitoHK-II on tBid is also downstream of Akt, contributing to Akt-mediated protection.…”

Section: Akt and Mitochondrial Hk-ii In Protectionmentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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“…PTEN-Akt signaling regulates the stem cell/progenitor cell homeostasis (Cully et al, 2006;Oudit and Penninger, 2009;Sussman et al, 2011;Walsh, 2006). In several stem/progenitor cell systems, such as hematopoietic stem cells, intestinal stem cells (ISCs) and neural progenitor cells, deletion of Pten causes increased cell proliferation through Akt activation (Groszer et al, 2001;He et al, 2007;Li and Clevers, 2010).…”

Section: Introductionmentioning

confidence: 99%

Akt1 signaling coordinates BMP signaling and β-catenin activity to regulate second heart field progenitor development

et al. 2015

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Second heart field (SHF) progenitors exhibit continued proliferation and delayed differentiation, which are modulated by FGF4/8/10, BMP and canonical Wnt/β-catenin signaling. PTEN-Akt signaling regulates the stem cell/progenitor cell homeostasis in several systems, such as hematopoietic stem cells, intestinal stem cells and neural progenitor cells. To address whether PTEN-Akt signaling is involved in regulating cardiac progenitors, we deleted Pten in SHF progenitors. Deletion of Pten caused SHF expansion and increased the size of the SHF derivatives, the right ventricle and the outflow tract. Cell proliferation of cardiac progenitors was enhanced, whereas cardiac differentiation was unaffected by Pten deletion. Removal of Akt1 rescued the phenotype and early lethality of Pten deletion mice, suggesting that Akt1 was the key downstream target that was negatively regulated by PTEN in cardiac progenitors. Furthermore, we found that inhibition of FOXO by Akt1 suppressed the expression of the gene encoding the BMP ligand (BMP7), leading to dampened BMP signaling in the hearts of Pten deletion mice. Cardiac activation of Akt also increased the Ser552 phosphorylation of β-catenin, thus enhancing its activity. Reducing β-catenin levels could partially rescue heart defects of Pten deletion mice. We conclude that Akt signaling regulates the cell proliferation of SHF progenitors through coordination of BMP signaling and β-catenin activity.

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“…These studies revealed a fundamental mechanism for endogenous kinase activation of PI-3K and Akt that is entirely dependent on IRS-1 and -2 or insulin and IGF-1 in the heart. Many other growth factors, such as VEGF and PDGF, are capable of activating PI-3K and Akt in cells (Sussman et al 2011). For example, PDGF activates Akt in an IRS-independent manner in mouse embryonic fibroblasts, as we previously demonstrated (Guo et al 2006).…”

Section: :3mentioning

confidence: 51%

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

Guo

2017

Journal of Endocrinology

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The heart is an insulin-dependent and energy-consuming organ in which insulin and nutritional signaling integrates to the regulation of cardiac metabolism, growth and survival. Heart failure is highly associated with insulin resistance, and heart failure patients suffer from the cardiac energy deficiency and structural and functional dysfunction. Chronic pathological conditions, such as obesity and type 2 diabetes mellitus, involve various mechanisms in promoting heart failure by remodeling metabolic pathways, modulating cardiac energetics and impairing cardiac contractility. Recent studies demonstrated that insulin receptor substrates 1 and 2 (IRS-1,-2) are major mediators of both insulin and insulin-like growth factor-1 (IGF-1) signaling responsible for myocardial energetics, structure, function and organismal survival. Importantly, the insulin receptor substrates (IRS) play an important role in the activation of the phosphatidylinositide-3-dependent kinase (PI-3K) that controls Akt and Foxo1 signaling cascade, regulating the mitochondrial function, cardiac energy metabolism and the renin-angiotensin system. Dysregulation of this branch in signaling cascades by insulin resistance in the heart through the endocrine system promotes heart failure, providing a novel mechanism for diabetic cardiomyopathy. Therefore, targeting this branch of IRS→PI-3K→Foxo1 signaling cascade and associated pathways may provide a fundamental strategy for the therapeutic and nutritional development in control of metabolic and cardiovascular diseases. In this review, we focus on insulin signaling and resistance in the heart and the role energetics play in cardiac metabolism, structure and function.

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Myocardial AKT: The Omnipresent Nexus

Cited by 199 publications

References 681 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Akt1 signaling coordinates BMP signaling and β-catenin activity to regulate second heart field progenitor development

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

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