GSK3β: A master switch and a promising target

Kannoji, Akanksha; Phukan, Samiron; Babu, V Sudher; Balaji, V.

doi:10.1517/14728222.12.11.1443

Cited by 31 publications

(25 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1). GSK-3β is highly expressed in the mature brain and has been implicated in many diseases (19,20). One recent study showed that GSK-3β mediates LTD formation (11).…”

Section: Discussionmentioning

confidence: 99%

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

Wei

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

114

View full text Add to dashboard Cite

Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK-3β, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3β capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders.α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor | internalization | kinesin light chain 2

show abstract

“…S1). GSK-3β is highly expressed in the mature brain and has been implicated in many diseases (19,20). One recent study showed that GSK-3β mediates LTD formation (11).…”

Section: Discussionmentioning

confidence: 99%

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

Wei

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

114

View full text Add to dashboard Cite

show abstract

“…3). GSK3β is a multifunctional serine/threonine kinase, which plays a major role in various signaling pathways [68]. GSK3β phosphorylates Fyn, a tyrosine kinase, at unknown threonine residue(s) leading to nuclear localization of Fyn [69].…”

Section: Other Regulatory Mediators Of Nrf2mentioning

confidence: 99%

Nrf2:INrf2 (Keap1) signaling in oxidative stress

Kaspar

Niture

Jaiswal

2009

Free Radical Biology and Medicine

1,443

1,066

View full text Add to dashboard Cite

Nrf2:INrf2(Keap1) are cellular sensors of chemical and radiation induced oxidative and electrophilic stress. Nrf2 is a nuclear transcription factor that controls the expression and coordinated induction of a battery of defensive genes encoding detoxifying enzymes and antioxidant proteins. This is a mechanism of critical importance for cellular protection and cell survival. Nrf2 is retained in the cytoplasm by an inhibitor INrf2. INrf2 functions as an adapter for Cul3/Rbx1 mediated degradation of Nrf2. In response to oxidative/electrophilic stress, Nrf2 is switched on and then off by distinct early and delayed mechanisms. Oxidative/electrophilic modification of INrf2cysteine151 and/or PKC phosphorylation of Nrf2serine40 results in the escape or release of Nrf2 from INrf2. Nrf2 is stabilized and translocates to the nucleus, forms heterodimers with unknown proteins, and binds antioxidant response element (ARE) that leads to coordinated activation of gene expression. It takes less than fifteen minutes from the time of exposure to switch on nuclear import of Nrf2. This is followed by activation of a delayed mechanism that controls switching off of Nrf2 activation of gene expression. GSK3β phosphorylates Fyn at unknown threonine residue(s) leading to nuclear localization of Fyn. Fyn phosphorylates Nrf2tyrosine568 resulting in nuclear export of Nrf2, binding with INrf2 and degradation of Nrf2. The switching on and off of Nrf2 protect cells against free radical damage, prevents apoptosis and promotes cell survival.

show abstract

“…It is also an important component of diverse signaling pathways including Wnt/β-catenin, insulin, Notch, and Hedgehog signaling pathways [46]. Studies show that it plays a critical role in the development and progression of various malignancies.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-101 reverses temozolomide resistance by inhibition of GSK3β in glioblastoma

Tian

Xia

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is a chemotherapy-resistant brain tumor with limited treatment options. Temozolomide (TMZ), an alkylating agent, is a front-line chemotherapeutic drug currently employed in GBM. Although it is currently the most promising chemotherapy for GBM, resistance to TMZ is also common and accounts for many treatment failures. Therefore, understanding the underlying mechanisms that generate resistance is essential to develop more effective chemotherapies. Here, we show that microRNA-101 (miR-101) was significantly downregulated in TMZ-resistant GBM cells and human specimens. Instead, over-expression of miR-101 could sensitize resistant GBM cells to TMZ through downregulation of glycogen synthase kinase 3β (GSK3β). Moreover, we found that GSK3β inhibition could enhance TMZ effect through repression of MGMT via promoter methylation. Importantly, decreased expression of miR-101 is related to poor prognosis in patients with GBM, suggesting its potential role as a new prognostic marker in GBM. In conclusion, our study demonstrates that miR-101 can reverse TMZ resistance by inhibition of GSK3β in GBM, thus offer a novel and powerful strategy for GBM therapy.

show abstract

GSK3β: A master switch and a promising target

Cited by 31 publications

References 91 publications

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

Nrf2:INrf2 (Keap1) signaling in oxidative stress

MicroRNA-101 reverses temozolomide resistance by inhibition of GSK3β in glioblastoma

Contact Info

Product

Resources

About