Akt-independent GSK3 inactivation downstream of PI3K signaling regulates mammalian axon regeneration

Zhang, Bo Yin; Saijilafu,; Liu, Chang Mei; Wang, Rui Ying; Zhu, Qiang; Jiao, Zhongxian; Zhou, Feng

doi:10.1016/j.bbrc.2013.12.037

Cited by 37 publications

(42 citation statements)

References 15 publications

(28 reference statements)

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“…Taken together these findings suggest that the appearance of UDP-hexoses peak requires modulation of another pathway besides AKT/mTORC1 and that the level of p-GSK-3 expression does not necessarily affect UDP-hexose content. A recent study has shown that PI3K suppresses the activity of GSK3 by an Akt-independent pathway16 and that inhibition with LY294002 activates GSK3.…”

Section: Discussionmentioning

confidence: 99%

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Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3

Phyu¹,

Tseng²,

Fleming³

et al. 2016

Sci Rep

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Akt is an intracellular signalling pathway that serves as an essential link between cell surface receptors and cellular processes including proliferation, development and survival. The pathway has many downstream targets including glycogen synthase kinase3 which is a major regulatory kinase for cell cycle transit as well as controlling glycogen synthase activity. The Akt pathway is frequently up-regulated in cancer due to overexpression of receptors such as the epidermal growth factor receptor, or mutation of signalling pathway kinases resulting in inappropriate survival and proliferation. Consequently anticancer drugs have been developed that target this pathway. MDA-MB-468 breast and HCT8 colorectal cancer cells were treated with inhibitors including LY294002, MK2206, rapamycin, AZD8055 targeting key kinases in/associated with Akt pathway and the consistency of changes in 31P-NMR-detecatable metabolite content of tumour cells was examined. Treatment with the Akt inhibitor MK2206 reduced phosphocholine levels in MDA-MB-468 cells. Treatment with either the phosphoinositide-3-kinase inhibitor, LY294002 and pan-mTOR inhibitor, AZD8055 but not pan-Akt inhibitor MK2206 increased uridine-5′-diphosphate-hexose cell content which was suppressed by co-treatment with glycogen synthase kinase 3 inhibitor SB216763. This suggests that there is an Akt-independent link between phosphoinositol-3-kinase and glycogen synthase kinase3 and demonstrates the potential of 31P-NMR to probe intracellular signalling pathways.

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Section: Discussionmentioning

confidence: 99%

“…It has been shown that GSK can be controlled by PI3K via PKA which physically complexes with GSK15. Recently a further Akt-independent link between PI3K and GSK3 has been identified16.…”

mentioning

confidence: 99%

Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3

Phyu¹,

Tseng²,

Fleming³

et al. 2016

Sci Rep

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show abstract

“…For example, serum- and glucocorticoid-inducible kinase 1 (SGK1) stimulates potassium channel Kv7.1 via Akt-independent PI3K signaling in kidney epithelial cells [29]. Akt-independent inactivation of GSK3, a downstream target of PI3K upon peripheral nerve injury may be required for neuronal regeneration [30]. To regulate the proliferation of melanoma cells, BRAF N600E and PI3K signaling cooperated through Akt-independent effects on protein translation in human melanoma cell lines [31].…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochondrial adaptations

Noh

Wende

Olsen

et al. 2015

Journal of Molecular and Cellular Cardiology

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Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase of mitochondrial oxidative capacity to physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1+/−) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1+/− mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1+/− mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1+/− mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.2 ± 0.2 vs. 7.1 ± 0.2, P=0.001), but not in cPDPK1+/− (6.2 ± 0.3 vs. 6.5 ± 0.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.7 ± 0.1 vs. 4.0 ± 0.1 mm, P=0.01) but not in cPDPK1+/− (3.8 ± 0.1 vs. 3.7 ± 0.1 mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.6 ± 0.6 vs.16.1 ± 0.9, P=0.04; cPDPK1+/−: 12.4 ± 0.6 vs.15.9 ± 1.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function.

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“…It regulates both axon establishment and elongation both during development and in the regeneration of mature neurons through glycogen synthase kinase 3 (GSK3). However, the mechanism of GSK3 control of peripheral axon regeneration is controversial and its function in CNS axon regeneration remains unknown (Jiang et al, 2005; Yoshimura et al, 2006; Kim et al, 2011; Saijilafu et al, 2013; Zhang et al, 2014; Gobrecht et al, 2014). Moreover, Akt links a host of signaling molecules through activation of mTORC1, which regulates cap-dependent protein translation by inhibiting TSC1/2 to allow axon development, growth, and regeneration in CNS (Ma et al, 2008; Li et al, 2008; Morita and Sobue, 2009; Park et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Akt1-Inhibitor of DNA binding2 is essential for growth cone formation and axon growth and promotes central nervous system axon regeneration

Kwon

Hwang

et al. 2016

eLife

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Mechanistic studies of axon growth during development are beneficial to the search for neuron-intrinsic regulators of axon regeneration. Here, we discovered that, in the developing neuron from rat, Akt signaling regulates axon growth and growth cone formation through phosphorylation of serine 14 (S14) on Inhibitor of DNA binding 2 (Id2). This enhances Id2 protein stability by means of escape from proteasomal degradation, and steers its localization to the growth cone, where Id2 interacts with radixin that is critical for growth cone formation. Knockdown of Id2, or abrogation of Id2 phosphorylation at S14, greatly impairs axon growth and the architecture of growth cone. Intriguingly, reinstatement of Akt/Id2 signaling after injury in mouse hippocampal slices redeemed growth promoting ability, leading to obvious axon regeneration. Our results suggest that Akt/Id2 signaling is a key module for growth cone formation and axon growth, and its augmentation plays a potential role in CNS axonal regeneration.DOI: http://dx.doi.org/10.7554/eLife.20799.001

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Akt-independent GSK3 inactivation downstream of PI3K signaling regulates mammalian axon regeneration

Cited by 37 publications

References 15 publications

Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3

Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3

Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochondrial adaptations

Akt1-Inhibitor of DNA binding2 is essential for growth cone formation and axon growth and promotes central nervous system axon regeneration

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