Glycogen synthase kinase‐3 and alternative splicing

Klein, Peter S.

doi:10.1002/wrna.1501

Cited by 25 publications

(22 citation statements)

References 159 publications

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“…The catalytically active regions of these two subtypes exhibit 97% sequence homology. Furthermore, GSK-3alpha and GSK-3beta are widely expressed in cells and tissues and have similar biological characteristics [45]. Recent studies have found that GSK-3beta can phosphorylate many endogenous substrates, including numerous proteins and transcription factors involved in metabolism.…”

Section: Akt Target Proteinsmentioning

confidence: 99%

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

et al. 2020

Cell Biosci

469

263

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The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.

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Section: Akt Target Proteinsmentioning

confidence: 99%

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

et al. 2020

Cell Biosci

469

263

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“…With more than 40 definitely identified targets and more than 500 proposed candidate substrates, GSK3 is involved in the regulation of a plethora of intracellular/molecular, organic/cellular, and (patho-)physiological events [1]. For instance, GSK3 has an influence on transcriptional regulation, alternative splicing [2,3], and mRNA stability [4]. On the protein level, GSK3 affects translation and protein synthesis [5,6], protein activity, localization, and degradation [7] (including its participation in the β-catenin destruction complex [8]).…”

Section: Introductionmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

101

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GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.

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“…GSK3 contributes to the regulation of many proteins implicated in a wide range of cellular functions [11][12][13][14] . Which GSK3 substrate(s) may be most relevant to the mood and cognitive enhancing properties of GSK3 inhibition by lithium remains unclear and none have been unambiguously associated with the mood and cognitive enhancing properties of GSK3β inhibition.…”

Section: Introductionmentioning

confidence: 99%

Discovery of suppressors of CRMP2 phosphorylation reveals compounds that mimic the behavioral effects of lithium on amphetamine-induced hyperlocomotion

et al. 2020

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The effective treatment of bipolar disorder (BD) represents a significant unmet medical need. Although lithium remains a mainstay of treatment for BD, limited knowledge regarding how it modulates affective behavior has proven an obstacle to discovering more effective mood stabilizers with fewer adverse side effects. One potential mechanism of action of lithium is through inhibition of the serine/threonine protein kinase GSK3β, however, relevant substrates whose change in phosphorylation may mediate downstream changes in neuroplasticity remain poorly understood. Here, we used human induced pluripotent stem cell (hiPSC)-derived neuronal cells and stable isotope labeling by amino acids in cell culture (SILAC) along with quantitative mass spectrometry to identify global changes in the phosphoproteome upon inhibition of GSK3α/β with the highly selective, ATP-competitive inhibitor CHIR-99021. Comparison of phosphorylation changes to those induced by therapeutically relevant doses of lithium treatment led to the identification of collapsin response mediator protein 2 (CRMP2) as being highly sensitive to both treatments as well as an extended panel of structurally distinct GSK3α/β inhibitors. On this basis, a high-content image-based assay in hiPSC-derived neurons was developed to screen diverse compounds, including FDA-approved drugs, for their ability to mimic lithium's suppression of CRMP2 phosphorylation without directly inhibiting GSK3β kinase activity. Systemic administration of a subset of these CRMP2-phosphorylation suppressors were found to mimic lithium's attenuation of amphetamine-induced hyperlocomotion in mice. Taken together, these studies not only provide insights into the neural substrates regulated by lithium, but also provide novel human neuronal assays for supporting the development of mechanism-based therapeutics for BD and related neuropsychiatric disorders.

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Glycogen synthase kinase‐3 and alternative splicing

Cited by 25 publications

References 159 publications

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Discovery of suppressors of CRMP2 phosphorylation reveals compounds that mimic the behavioral effects of lithium on amphetamine-induced hyperlocomotion

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