GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways

Avrahami, Limor; Paz, Rom; Dominko, Kristina; Hečimović, Silva; Bucci, Cecilia; Eldar-Finkelman, Hagit

doi:10.1016/j.cellsig.2020.109597

Cited by 19 publications

(21 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GSK-3β can phosphorylate TSC2, and phosphorylation of TSC2 further translocates from the lysosomal surface and stimulates mTOR1 by way of the GTPase-activating protein Rheb [ 12 , 13 ]. GSK-3β is a multi-functional enzyme blocking the lysosome activation and autophagy via mTOR [ 14 , 15 ]. Overactivation of GSK-3β and mTOR1 has been implicated in aging and its associated diseases.…”

Section: Introductionmentioning

confidence: 99%

“…A decline in the lysosome-associated autophagic process escalates damaged protein accumulation, which is directly responsible for cellular senescence and ageing. Intensifying the lysosomal biogenesis and autophagic degradation by deactivating the GSK-3β will continually advance protein synthesis, cell differentiation and growth and prevent cell senescence [ 15 , 16 , 17 ]. The accumulation and expression of GSK-3β is lethal to various types of cells which induce senescence and apoptosis [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence

Rethineswaran

Kim

et al. 2021

IJMS

View full text Add to dashboard Cite

Endothelial progenitor cells (EPCs) are specialized cells in circulating blood, well known for their ability to form new vascular structures. Aging and various ailments such as diabetes, atherosclerosis and cardiovascular disease make EPCs vulnerable to decreasing in number, which affects their migration, proliferation and angiogenesis. Myocardial ischemia is also linked to a reduced number of EPCs and their endothelial functional role, which hinders proper blood circulation to the myocardium. The current study shows that an aminopyrimidine derivative compound (CHIR99021) induces the inhibition of GSK-3β in cultured late EPCs. GSK-3β inhibition subsequently inhibits mTOR by blocking the phosphorylation of TSC2 and lysosomal localization of mTOR. Furthermore, suppression of GSK-3β activity considerably increased lysosomal activation and autophagy. The activation of lysosomes and autophagy by GSK-3β inhibition not only prevented replicative senescence of the late EPCs but also directed their migration, proliferation and angiogenesis. To conclude, our results demonstrate that lysosome activation and autophagy play a crucial role in blocking the replicative senescence of EPCs and in increasing their endothelial function. Thus, the findings provide an insight towards the treatment of ischemia-associated cardiovascular diseases based on the role of late EPCs.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence

Rethineswaran

Kim

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Deficiency of autophagylysosomal pathway, leading to dysfunction of protein aggregate clearance, was observed in post-mortem brains of PD patients and PD animal models (Meredith et al, 2002;Crews et al, 2010;Dehay et al, 2010;Vila et al, 2011;Bové et al, 2014). Increasing evidence suggests that GSK-3β inhibition restored lysosomal acidification and biogenesis by mediating nuclear translocation of Transcription Factor EB (TFEB) or through GSK-3β/tuberous sclerosis complex (TSC) axis, and thus showed neuroprotective effects in pathological conditions (Avrahami et al, 2013(Avrahami et al, , 2020Azoulay-Alfaguter et al, 2015;Marchand et al, 2015;Li Y. et al, 2016;Ren et al, 2018). In addition, some substrates, such as α-synuclein and Tau, whose phosphorylation by GSK-3β may progressively lead to intracellular and axonal deposit, may be involved in GSK-3βmediated parkinsonian pathophysiology (Credle et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib

Chen

et al. 2020

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Glycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson's disease (PD). The two isoforms, GSK-3α and GSK-3β, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3β on PD pathogenesis, while the role of GSK-3α has been largely overlooked. Here, we report in situ observations that both GSK-3α and GSK-3β are dephosphorylated at a negatively acting regulatory serine, indicating kinase activation, selectively in nigral dopaminergic neurons following exposure of mice to 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP). To identify whether GSK-3α and GSK-3β display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3a Dat ) and Gsk3b null (Gsk3b Dat ) mice, respectively. We found that Gsk3b Dat , but not Gsk3a Dat , showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3α and GSK-3β in PD pathogenesis. In addition, we tested the neuroprotective effect of tideglusib, the most clinically advanced inhibitor of GSK-3, in the MPTP model of PD. Administration of higher doses (200 mg/kg and 500 mg/kg) of tideglusib exhibited significant neuroprotection, whereas 50 mg/kg tideglusib failed to prevent dopaminergic neurodegeneration from MPTP toxicity. Administration of 200 mg/kg tideglusib improved motor symptoms of MPTP-treated mice. Together, these data demonstrate GSK-3β and not GSK-3α is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3β acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.

show abstract

“…TMEM9 levels were elevated in colorectal cancer and hepatocellular carcinoma cell lines, and contributed to tumorigenesis through Wnt signaling, in a V-ATPasedependent manner (Jung et al, 2018(Jung et al, , 2020. Interestingly, GSK3 inhibition with chemical inhibitors or siRNA was also found to enhance endolysosomal acidification through increased autophagic activity and endosomal maturation, in cultured cancer cells and mouse models for Alzheimer disease (Avrahami et al, 2013(Avrahami et al, , 2020Azoulay-Alfaguter et al, 2015). Thus, it is possible that modulation of GSK3 activity by Wnt plays a key role in endosome acidification and biogenesis.…”

Section: Add Iti Onal Fac Tor S Requ Ired For S I G Nalosome Endo Cmentioning

confidence: 99%

Wnt/β‐catenin signaling: Structure, assembly and endocytosis of the signalosome

Colozza

Koo

2021

Dev Growth Differ

View full text Add to dashboard Cite

Wnt signaling is an evolutionarily conserved pathway involved in embryonic development and cell differentiation (Nusse & Clevers, 2017).In addition, it regulates many other processes, including cell growth and mitosis, adult stem cell homeostasis, and regeneration (Acebron & Niehrs, 2016;Nusse & Clevers, 2017;Reddien, 2018). Aberrant activation of the Wnt pathway lies at the basis of different types of malignancies, including colorectal, breast, and hepatic cancers.Historically, the first Wnt gene was identified in Drosophila melanogaster, following a screen for recessive mutant genes that affect segment patterning of fruit fly embryos. Because the mutant flies did not develop wings, the gene was named wingless (wg) (Sharma, 1973;Sharma & Chopra, 1976). Years later, the proto-oncogene integration site-1 (int-1) was discovered while studying mouse models of mammary carcinomas induced by DNA integrations of the mouse mammary tumor virus (MMTV) (Nusse & Varmus, 1982). Since Int-1 was found to be the mammalian orthologue of Wg, it was then renamed Wnt1 (Wingless + Int1) (Nusse et al., 1991).Wnts are secreted glycoproteins (Brown et al., 1987;Papkoff et al., 1987) that can activate divergent pathways, classically categorized as: (a) the canonical or β-catenin dependent pathway; and (b) the noncanonical branch, comprising the planar cell polarity and Ca 2+ pathways. Although some Wnts preferentially activate one or the other pathway, their specificity is less strict than previously thought and likely depends on the cell-specific context and the repertoire of receptors and components expressed, rather than on intrinsic properties. Indeed, while the serpentine Frizzled (Fzd) receptors are a shared component of all Wnt pathways, coreceptors such as the low-density lipoprotein receptor-related protein 5 and 6 (Lrp5/6;

show abstract

GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways

Cited by 19 publications

References 93 publications

CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence

CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence

GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib

Wnt/β‐catenin signaling: Structure, assembly and endocytosis of the signalosome

Contact Info

Product

Resources

About