X MARCKS the spot: myristoylated alanine-rich C kinase substrate in neuronal function and disease

Brudvig, Jon; Weimer, Jill M.

doi:10.3389/fncel.2015.00407

Cited by 51 publications

(70 citation statements)

References 97 publications

(160 reference statements)

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“…Proteins affected by CYP46A1 activation and Cyp46a1 ablation were also different, except CTNND2, DPYSL2, GAP43, MAP1B, MAP6, MARCKS, PKP4, and SAMD14 ( Fig. 6B), which all pertain to neurite growth excluding SAMD14 (122)(123)(124)(125)(126)(127).…”

Section: Brain Phosphoproteomementioning

confidence: 99%

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Petrov

Mast

et al. 2019

FASEB j.

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Efavirenz (EFV) is an anti‐HIV drug, and cytochrome P450 46A1 (CYP46A1) is the major brain cholesterol hydroxylase. Previously, we discovered that EFV activates CYP46A1 and improves behavioral performance in 5XFAD mice, an Alzheimer's disease model. Herein, the unbiased omics and other approaches were used to study 5XFAD mice in the amyloid‐decreasing paradigm of CYP46A1 activation by EFV. These approaches revealed increases in the brain levels of postsynaptic density protein 95, gephyrin, synaptophysin, synapsin, glial fibrillary acidic protein, and CYP46A1 and documented altered expression and phosphorylation of 66 genes and 77 proteins, respectively. The data obtained pointed to EFV effects at the synaptic level, plasmin‐depended amyloid clearance, inflammation and microglia phenotype, oxidative stress and cellular hypoxia, autophagy and ubiquitin‐proteasome systems as well as apoptosis. These effects could be realized in part via changes in the Ca2+‐, small GTPase, and catenin signaling. A model is proposed, in which CYP46A1‐dependent lipid raft rearrangement and subsequent decrease of protein phosphorylation are central in EFV effects and explain behavioral improvements in EFV‐treated 5XFAD mice.—Petrov, A. M., Mast, N., Li, Y., Pikuleva, I. A. The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment. FASEB J. 33, 8782–8798 (2019). http://www.fasebj.org

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Section: Brain Phosphoproteomementioning

confidence: 99%

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Petrov

Mast

et al. 2019

FASEB j.

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“…It has since become one of the most robust and well characterized read-outs of conventional and novel PKC signaling [49]. Its deletion in mice has revealed that it is required for mouse brain development and postnatal survival [50].…”

Section: Regulation Of the Cytoskeleton: Marcks Gap43 And Taumentioning

confidence: 99%

“…PKC has also been linked to N-methyl-d-aspartate receptor (NMDAR)-mediated reduction in tau phosphorylation [69]. Overall, PKC's regulation of cytoskeleton dynamics in the brain plays a critical role not only in synapse formation and maintenance, but also in the functions of non-neuronal cells such as endothelial and glial cells [49].…”

Section: Regulation Of the Cytoskeleton: Marcks Gap43 And Taumentioning

confidence: 99%

Conventional protein kinase C in the brain: 40 years later

Callender

Newton

2017

Neuronal Signaling

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Protein kinase C (PKC) is a family of enzymes whose members transduce a large variety of cellular signals instigated by the receptor-mediated hydrolysis of membrane phospholipids. While PKC has been widely implicated in the pathology of diseases affecting all areas of physiology including cancer, diabetes, and heart disease -it was discovered, and initially characterized, in the brain. PKC plays a key role in controlling the balance between cell survival and cell death. Its loss of function is generally associated with cancer, whereas its enhanced activity is associated with neurodegeneration. This review presents an overview of signaling by diacylglycerol (DG)-dependent PKC isozymes in the brain, and focuses on the role of the Ca 2 + -sensitive conventional PKC isozymes in neurodegeneration.

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“…However, MeHg exposure elicited a biphasic increase in MARCKS phosphorylation, and significant differences were observed at concentrations higher than 0.3 µ M at 24 hr after the treatment. Since the interactions between MARCKS and its target molecules, such as actin and phosphatidylinositol 4,5-bisphosphate, are regulated by phosphorylation at the effector domain of MARCKS [3, 17], it is likely that the phosphorylation of MARCKS induced by MeHg is directly involved in the MeHg toxicity on EA.hy926 cells. MeHg is known to induce reactive oxygen species (ROS) production, including hydrogen peroxide (H 2 O 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…Homozygous mutant mice with targeted deletion of the Marcks gene showed morphological abnormalities in the central nervous system and perinatal death [39], suggesting the essential role of MARCKS in brain development. MARCKS plays roles in cellular functions, such as adhesion, migration, proliferation and fusion in multiple types of cells through its interaction with the membrane phospholipids and actin, which is regulated by phosphorylation at the central polybasic region of MARCKS called the effector domain [2, 3, 27, 48]. In vascular smooth muscle and endothelial cells, MARCKS has been shown to regulate proliferation [46], cell migration [17, 26, 47] and endothelial cell permeability [16].…”

mentioning

confidence: 99%

MARCKS is involved in methylmercury-induced decrease in cell viability and nitric oxide production in EA.hy926 cells

Dao

Islam

Sudo

et al. 2016

The Journal of Veterinary Medical Science

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Methylmercury (MeHg) is a persistent environmental contaminant that has been reported worldwide. MeHg exposure has been reported to lead to increased risk of cardiovascular diseases; however, the mechanisms underlying the toxic effects of MeHg on the cardiovascular system have not been well elucidated. We have previously reported that mice exposed to MeHg had increased blood pressure along with impaired endothelium-dependent vasodilation. In this study, we investigated the toxic effects of MeHg on a human endothelial cell line, EA.hy926. In addition, we have tried to elucidate the role of myristoylated alanine-rich C kinase substrate (MARCKS) in the MeHg toxicity mechanism in EA.hy926 cells. Cells exposed to MeHg (0.1–10 µM) for 24 hr showed decreased cell viability in a dose-dependent manner. Treatment with submaximal concentrations of MeHg decreased cell migration in the wound healing assay, tube formation on Matrigel and spontaneous nitric oxide (NO) production of EA.hy926 cells. MeHg exposure also elicited a decrease in MARCKS expression and an increase in MARCKS phosphorylation. MARCKS knockdown or MARCKS overexpression in EA.hy926 cells altered not only cell functions, such as migration, tube formation and NO production, but also MeHg-induced decrease in cell viability and NO production. These results suggest the broad role played by MARCKS in endothelial cell functions and the involvement of MARCKS in MeHg-induced toxicity.

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X MARCKS the spot: myristoylated alanine-rich C kinase substrate in neuronal function and disease

Cited by 51 publications

References 97 publications

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Conventional protein kinase C in the brain: 40 years later

MARCKS is involved in methylmercury-induced decrease in cell viability and nitric oxide production in EA.hy926 cells

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