Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

Gopalakrishnan, Ramakrishnan; Davaakhuu, Gantulga; Kaplun, Ludmila; Chung, W. C.; Rana, Ajay; Atfi, Azeddine; Miele, Lucio; Tzivion, Guri

doi:10.1074/jbc.m113.537266

Cited by 106 publications

(87 citation statements)

References 48 publications

(67 reference statements)

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“…In addition to SIRT1, also SIRT2 can physically interact with Akt; the sirtuins may be exchanged depending on the activation state of the IIS pathways. SIRT2 is necessary for full activation of Akt in response to insulin/growth factor signalling, while a deficient Akt response is noted in metabolic disturbances including insulin resistance [164]. Together with the above-mentioned results it suggests an image of extremely tightly regulated, multi-level influence of SIRT2 on FOXO-mediated events.…”

Section: Transcriptional and Post-transcriptional Regulators As Sirtumentioning

confidence: 57%

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

Jęśko¹,

Strosznajder²

2016

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A b s t r a c tSirtuins vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-κB, and DNA-PK (DNA-dependent protein kinase). Sirtuins also interact extensively with the family of poly(ADPribose) polymerases (PARPs), a crucial and widespread class of NAD

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Section: Transcriptional and Post-transcriptional Regulators As Sirtumentioning

confidence: 57%

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

Jęśko¹,

Strosznajder²

2016

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“…A recent study indicated that deacetylation by SIRT1 enhances binding of AKT and PDK1 to PIP 3 and promotes their activation, whereas SIRT1 inhibitor-mediated acetylation of AKT and PDK1 reduces binding of AKT and PDK1 to PIP 3 , resulting in prevention of AKT phosphorylation (Sundaresan et al, 2011). Similarly, a recent study showed that SIRT2 directly interacts with AKT and is required for optimal activation of AKT (Ramakrishnan et al, 2014). Together with Fig.…”

Section: Sirt1/2 Mediates Renal Fibrosismentioning

confidence: 63%

Blocking Sirtuin 1 and 2 Inhibits Renal Interstitial Fibroblast Activation and Attenuates Renal Interstitial Fibrosis in Obstructive Nephropathy

Ponnusamy¹,

Zhou²,

Yan³

et al. 2014

J Pharmacol Exp Ther

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Our recent studies revealed that blocking class I/II histone deacetylases (HDACs) inhibits renal interstitial fibroblast activation and proliferation and alleviates development of renal fibrosis. However, the effect of class III HDAC, particularly sirtuin 1 and 2 (SIRT1 and SIRT2), inhibition on renal fibrogenesis remains elusive. Here, we demonstrate that both SIRT1 and SIRT2 were expressed in cultured renal interstitial fibroblasts (NRK-49F). Exposure of NRK-49F to sirtinol, a selective inhibitor of SIRT1/2, or EX527 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide), an inhibitor for SIRT1, resulted in reduced expression of fibroblast activation markers (a-smooth muscle actin, fibronectin, and collagen I) as well as proliferation markers (proliferating cell nuclear antigen, cyclin D1, cyclin E) in dose-and timedependent manners. Treatment with a SIRT2 inhibitor, AGK2 (2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide), also dose-and time-dependently inhibited renal fibroblast activation and, to a lesser extent, cell proliferation. Furthermore, silencing of either SIRT1 or SIRT2 by small interfering RNA exhibited similar inhibitory effects. In a mouse model of obstructive nephropathy, administration of sirtinol attenuated deposition of collagen fibrils as well as reduced expression of a-smooth muscle actin, collagen

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“…Acetylation of Akt at residue Lys20 prevents plasma membrane localization and activation of Akt by phosphatidylinositol 3-kinase (PI3K) (Sundaresan et al, 2011), whereas deacetylation of Akt by Sirt2 is reported to promote its activity Dan et al, 2012). It has been previously suggested that phosphorylation of Thr101 on Sirt2 by AMPK is required for an Akt-Sirt2 interaction and subsequent activation by PI3K upon insulin signaling (Ramakrishnan et al, 2014). However, using the Akt inhibitor SC-66, we were unable to demonstrate the above Akt involvement in our model system.…”

Section: Discussionmentioning

confidence: 99%

“…A potential downstream target of Sirt2 is Akt, which is involved in insulin signaling and promotes a glycolytic phenotype in various cell types (Elstrom et al, 2004;Higaki et al, 2008;Ramakrishnan et al, 2014). Acetylation of Akt at residue Lys20 prevents plasma membrane localization and activation of Akt by phosphatidylinositol 3-kinase (PI3K) (Sundaresan et al, 2011), whereas deacetylation of Akt by Sirt2 is reported to promote its activity Dan et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation of Glut1-mediated glucose uptake by acute OXPHOS inhibition requires the activity of mTOR-RAPTOR A previous study has suggested that AMPK can phosphorylate Sirt2 at Thr101 and that this phosphorylation is required for the interaction with the serine/threonine protein kinase Akt (of which there are three isoforms) (Ramakrishnan et al, 2014). This interaction between Sirt2 and Akt is required to allow optimal Akt activation.…”

Section: Stimulation Of Glut1-mediated Glucose Uptake By Acute Oxphosmentioning

confidence: 99%

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Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Liemburg-Apers

Wagenaars

Smeitink

et al. 2016

Journal of Cell Science

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Mitochondria play a central role in cellular energy production, and their dysfunction can trigger a compensatory increase in glycolytic flux to sustain cellular ATP levels. Here, we studied the mechanism of this homeostatic phenomenon in C2C12 myoblasts. Acute (30 min) mitoenergetic dysfunction induced by the mitochondrial inhibitors piericidin A and antimycin A stimulated Glut1-mediated glucose uptake without altering Glut1 (also known as SLC2A1) mRNA or plasma membrane levels. The serine/threonine liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK) played a central role in this stimulation. In contrast, ataxiatelangiectasia mutated (ATM; a potential AMPK kinase) and hydroethidium (HEt)-oxidizing reactive oxygen species (ROS; increased in piericidin-A-and antimycin-A-treated cells) appeared not to be involved in the stimulation of glucose uptake. Treatment with mitochondrial inhibitors increased NAD + and NADH levels (associated with a lower NAD + :NADH ratio) but did not affect the level of Glut1 acetylation. Stimulation of glucose uptake was greatly reduced by chemical inhibition of Sirt2 or mTOR-RAPTOR. We propose that mitochondrial dysfunction triggers LKB1-mediated AMPK activation, which stimulates Sirt2 phosphorylation, leading to activation of mTOR-RAPTOR and Glut1-mediated glucose uptake.

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Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

Cited by 106 publications

References 48 publications

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

Blocking Sirtuin 1 and 2 Inhibits Renal Interstitial Fibroblast Activation and Attenuates Renal Interstitial Fibrosis in Obstructive Nephropathy

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

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