Glycogen synthase kinase-3β regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not Src

Yao, Xiu-Qing; Zhang, Xiaoxue; Yin, Yajun; Liu, Bin; Luo, Danju; Liú, Dan; Chen, Ningning; Ni, Zhong-Fei; Wang, Xiong; Wang, Qun; Wang, Jian‐Zhi; Liu, Gong‐Ping

doi:10.1042/bj20110347

Cited by 41 publications

(25 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, PP2Ac plays an important role in the pathogenesis of DCM. It is interesting to note that PP2A is a substrate for GSK-3β in multiple cell types, such as HEK293 cells and N2a cells, and that activated GSK-3β can negatively regulate PP2Ac activity [11, 12]. Henriksen et al [13] reported that GSK-3β activity was increased in both diabetes and insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Ren

Zuo

et al. 2016

PLoS ONE

View full text Add to dashboard Cite

Recent studies reported that atorvastatin (ATOR) alleviated progression of experimental diabetic cardiomyopathy (DCM), possibly by protecting against apoptosis. However, the underlying mechanisms of this protective effect remain unclear. Therefore, our study investigated the role of the glycogen synthase kinase (GSK)-3β-protein phosphatase 2A(PP2A)-NF-κB signaling pathway in the anti-apoptotic and cardioprotective effects of ATOR on cardiomyocytes cultured in high glucose (HG) and in DCM. Our results showed that, in HG-cultured cardiomyocytes, phosphorylation of GSK-3β was decreased, while that of the PP2A catalytic subunit C (PP2Ac) and IKK/IкBα was increased, followed by NF-кB nuclear translocation and apoptosis. IKK/IкBα phosphorylation and NF-кB nuclear translocation were also increased by treatment of cells with okadaic acid (OA), a selective PP2A inhibitor, or by silencing PP2Ac expression. The opposite results were obtained by silencing GSK-3β expression, which resulted in PP2Ac activation. Furthermore, IKK/IкBα phosphorylation and NF-кB nuclear translocation were markedly inhibited and apoptosis attenuated in cells treated with ATOR. These effects occurred through inactivation of GSK-3β and subsequent activation of PP2Ac. They were abolished by treatment of cells with OA or PP2Ac siRNA. In mice with type 1 diabetes mellitus, treatment with ATOR, at 10 mg-kg−1-d−1, significantly suppressed GSK-3β activation, IKK/IкBα phosphorylation, NF-кB nuclear translocation and caspase-3 activation, while also activating PP2Ac. Finally, improvements in histological abnormalities, fibrosis, apoptosis and cardiac dysfunction were observed in diabetic mice treated with ATOR. These findings demonstrated that ATOR protected against HG-induced apoptosis in cardiomyocytes and alleviated experimental DCM by regulating the GSK-3β-PP2A-NF-κB signaling pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

“…It is interesting to note that PP2Ac inactivation, resulting from activated GSK-3β, was reported in both human embryonic kidney 293 (HEK293) cells and neuro2a (N2a) cells [11, 12]. Increased GSK-3β activity was found in diabetes and in insulin resistance [13].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Ren

Zuo

et al. 2016

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…It has been reported that p60v-src, p56 lck , epidermal growth factor receptors, and insulin receptors (IR) are involved in the regulation of tyrosine phosphorylation of PP2Ac (Barisic et al, 2010; Chen et al, 1992; Hu et al, 2009). A recent study has shown that glycogen synthase kinase-3β (GSK3β) regulates tyrosine phosphorylation and inactivation of PP2Ac, via protein tyrosine phosphatase 1B (Yao et al, 2011). The activation of GSK3β is regulated by the linear signaling cascade IR/IRS/PI3K/Akt (Frame and Cohen, 2001).…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid protects cardiomyocytes from high glucose‐induced apoptosis through inhibition of NF‐κB signaling Pathway

Nizamutdinova

Guleria

Singh

et al. 2012

Journal Cellular Physiology

View full text Add to dashboard Cite

We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6 and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets.

show abstract

“…PP2A has been reported to dephosphorylate GSK3β at Ser9 [281], and conversely, activation of GSK3β can inhibit PP2A [529]. Importantly, Akt inhibits GSK3β and hence plays a critical role in maintaining the balance between the activities of GSK3β and PP2A [94].…”

Section: Post-translational Modification Of Taumentioning

confidence: 99%

Roles of tau protein in health and disease

2017

View full text Add to dashboard Cite

Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies. Recent advances in our understanding of the multiple functions and different locations of tau inside and outside neurons have revealed novel insights into its importance in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability. The present review describes the physiological and pathophysiological properties of tau and how these relate to its distribution and functions in neurons. We highlight the post-translational modifications of tau, which are pivotal in defining and modulating tau localisation and its roles in health and disease. We include discussion of other pathologically relevant changes in tau, including mutation and aggregation, and how these aspects impinge on the propensity of tau to propagate, and potentially drive neuronal loss, in diseased brain. Finally, we describe the cascade of pathological events that may be driven by tau dysfunction, including impaired axonal transport, alterations in synapse and mitochondrial function, activation of the unfolded protein response and defective protein degradation. It is important to fully understand the range of neuronal functions attributed to tau, since this will provide vital information on its involvement in the development and pathogenesis of disease. Such knowledge will enable determination of which critical molecular pathways should be targeted by potential therapeutic agents developed for the treatment of tauopathies.

show abstract

Glycogen synthase kinase-3β regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not Src

Cited by 41 publications

References 63 publications

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Retinoic acid protects cardiomyocytes from high glucose‐induced apoptosis through inhibition of NF‐κB signaling Pathway

Roles of tau protein in health and disease

Contact Info

Product

Resources

About