Lithium induces autophagy by inhibiting inositol monophosphatase

Macroautophagy is a key pathway for the clearance of aggregate-prone cytosolic proteins. Currently, the only suitable pharmacologic strategy for up-regulating autophagy in mammalian cells is to use rapamycin, which inhibits the mammalian target of rapamycin (mTOR), a negative regulator of autophagy. Here we describe a novel mTOR-independent pathway that regulates autophagy. We show that lithium induces autophagy, and thereby, enhances the clearance of autophagy substrates, like mutant huntingtin and α-synucleins. This effect is not mediated by glycogen synthase kinase 3β inhibition. The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase and led to free inositol depletion. This, in turn, decreased myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest that the autophagy effect is mediated at the level of (or downstream of) lowered IP3, because it was abrogated by pharmacologic treatments that increased IP3. This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate.

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Early signalling events of autophagy

Essays in Biochemistry ◽

10.1042/bse0550001 ◽

2013 ◽

Vol 55 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Laura E. Gallagher ◽

Edmond Y.W. Chan

Keyword(s):

Protein Kinase ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Mammalian Cells ◽

Mammalian Target Of Rapamycin ◽

Interacting Protein ◽

The Core ◽

Autophagy Gene ◽

Autophagy Induction ◽

Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

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Phosphorylation of tau by glycogen synthase kinase-3β in intact mammalian cells: The effects on the organization and stability of microtubules

Neuroscience ◽

10.1016/0306-4522(96)00126-1 ◽

1996 ◽

Vol 73 (4) ◽

pp. 1145-1157 ◽

Cited By ~ 123

Author(s):

S. Lovestone ◽

C.L. Hartley ◽

J. Pearce ◽

B.H. Anderton

Keyword(s):

Mammalian Cells ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β

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Insulin Signaling in Bupivacaine-induced Cardiac Toxicity

Anesthesiology ◽

10.1097/aln.0000000000000974 ◽

2016 ◽

Vol 124 (2) ◽

pp. 428-442 ◽

Cited By ~ 17

Author(s):

Michael R. Fettiplace ◽

Katarzyna Kowal ◽

Richard Ripper ◽

Alexandria Young ◽

Kinga Lis ◽

...

Keyword(s):

Protein Kinase ◽

Tuberous Sclerosis ◽

Glycogen Synthase ◽

Mammalian Target Of Rapamycin ◽

Glycogen Synthase Kinase ◽

Target Of Rapamycin ◽

Reversible Inhibitor ◽

Glycogen Synthase Kinase 3Β ◽

Phosphorylated Akt ◽

The Impact

Abstract Background The impact of local anesthetics on the regulation of glucose homeostasis by protein kinase B (Akt) and 5′-adenosine monophosphate–activated protein kinase (AMPK) is unclear but important because of the implications for both local anesthetic toxicity and its reversal by IV lipid emulsion (ILE). Methods Sprague–Dawley rats received 10 mg/kg bupivacaine over 20 s followed by nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3β, AMPK, acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002—a reversible Pi3K inhibitor. Results Bupivacaine cardiotoxicity rapidly dephosphorylated Akt at S473 to 63 ± 5% of baseline and phosphorylated AMPK to 151 ± 19%. AMPK activation inhibited targets downstream of mammalian target of rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 to 31 ± 8% of baseline sensitized Akt signaling in hearts resulting in hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3β to 390 ± 64% and 293 ± 50% of baseline, respectively. Glycogen accumulated to 142 ± 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardiotoxicity, whereas pretreating with a reversible inhibitor delayed the onset of toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 ± 23% and 167 ± 10% of baseline, respectively, but did not interfere with AMPK or targets of mammalian target of rapamycin complex 1. Conclusion Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardiotoxicity and modulation of these pathways by ILE contributes to lipid resuscitation.

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Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812943116 ◽

2019 ◽

Vol 116 (8) ◽

pp. 2977-2986 ◽

Cited By ~ 4

Author(s):

Rituraj Pal ◽

Yan Xiong ◽

Marco Sardiello

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Mammalian Target Of Rapamycin ◽

Glycogen Storage ◽

Tumor Formation ◽

Negative Regulator ◽

Multiple Organs ◽

Genes Encoding

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment.

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Phosphorylation of tau by glycogen synthase kinase 3β in intact mammalian cells influences the stability of microtubules

Neuroscience Letters ◽

10.1016/s0304-3940(01)02206-6 ◽

2001 ◽

Vol 312 (3) ◽

pp. 141-144 ◽

Cited By ~ 49

Author(s):

Huachun Sang ◽

Zhonghua Lu ◽

Yulong Li ◽

Binggen Ru ◽

Wenqing Wang ◽

...

Keyword(s):

Mammalian Cells ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

The Stability

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Glycogen Synthase Kinase 3β Is a Negative Regulator of Growth Factor-induced Activation of the c-Jun N-terminal Kinase

Journal of Biological Chemistry ◽

10.1074/jbc.m408607200 ◽

2004 ◽

Vol 279 (49) ◽

pp. 51075-51081 ◽

Cited By ~ 34

Author(s):

Shuying Liu ◽

Shuangxing Yu ◽

Yutaka Hasegawa ◽

Ruth LaPushin ◽

Hong-Ji Xu ◽

...

Keyword(s):

Growth Factor ◽

Glycogen Synthase ◽

Negative Regulator ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β

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Glycogen Synthase Kinase-3β Is a Negative Regulator of Cardiomyocyte Hypertrophy

The Journal of Cell Biology ◽

10.1083/jcb.151.1.117 ◽

2000 ◽

Vol 151 (1) ◽

pp. 117-130 ◽

Cited By ~ 285

Author(s):

Syed Haq ◽

Gabriel Choukroun ◽

Zhao Bin Kang ◽

Hardeep Ranu ◽

Takashi Matsui ◽

...

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Cellular Response ◽

Glycogen Synthase ◽

Negative Regulator ◽

Glycogen Synthase Kinase ◽

Cardiomyocyte Hypertrophy ◽

Glycogen Synthase Kinase 3Β ◽

Activated T Cells ◽

Gsk 3Β

Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase–dependent protein kinase that phosphorylates GSK-3β on ser 9. Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3β as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.

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Axil, a Member of the Axin Family, Interacts with Both Glycogen Synthase Kinase 3β and β-Catenin and Inhibits Axis Formation ofXenopus Embryos

Molecular and Cellular Biology ◽

10.1128/mcb.18.5.2867 ◽

1998 ◽

Vol 18 (5) ◽

pp. 2867-2875 ◽

Cited By ~ 125

Author(s):

Hideki Yamamoto ◽

Shosei Kishida ◽

Takaaki Uochi ◽

Satoshi Ikeda ◽

Shinya Koyama ◽

...

Keyword(s):

Wnt Signaling ◽

Binding Site ◽

Glycogen Synthase ◽

Wnt Signaling Pathway ◽

Amino Acid Identity ◽

Negative Regulator ◽

Glycogen Synthase Kinase ◽

Axis Formation ◽

Glycogen Synthase Kinase 3Β ◽

Gsk 3Β

ABSTRACT Using a yeast two-hybrid method, we identified a novel protein which interacts with glycogen synthase kinase 3β (GSK-3β). This protein had 44% amino acid identity with Axin, a negative regulator of the Wnt signaling pathway.We designated this protein Axil for Axin like. Like Axin, Axil ventralized Xenopus embryos and inhibited Xwnt8-induced Xenopus axis duplication. Axil was phosphorylated by GSK-3β. Axil bound not only to GSK-3β but also to β-catenin, and the GSK-3β-binding site of Axil was distinct from the β-catenin-binding site. Furthermore, Axil enhanced GSK-3β-dependent phosphorylation of β-catenin. These results indicate that Axil negatively regulates the Wnt signaling pathway by mediating GSK-3β-dependent phosphorylation of β-catenin, thereby inhibiting axis formation.

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