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#34125978   // To Up

Phosphorylation of meprin β controls its cell surface abundance and subsequently diminishes ectodomain shedding.

Meprin β is a zinc-dependent metalloprotease exhibiting a unique cleavage specificity with strong preference for acidic amino acids at the cleavage site. Proteomic studies revealed a diverse substrate pool of meprin β including the interleukin-6 receptor (IL-6R) and the amyloid precursor protein (APP). Dysregulation of meprin β is often associated with pathological conditions such as chronic inflammation, fibrosis, or Alzheimer's disease (AD). The extracellular regulation of meprin β including interactors, sheddases, and activators has been intensively investigated while intracellular regulation has been barely addressed in the literature. This study aimed to analyze C-terminal phosphorylation of meprin β with regard to cell surface expression and proteolytic activity. By immunoprecipitation of endogenous meprin β from the colon cancer cell line Colo320 and subsequent LC-MS analysis, we identified several phosphorylation sites in its C-terminal region. Here, T694 in the C-terminus of meprin β was the most preferred residue after phorbol 12-myristate 13-acetate (PMA) stimulation. We further demonstrated the role of protein kinase C (PKC) isoforms for meprin β phosphorylation and identified the involvement of PKC-α and PKC-β. As a result of phosphorylation, the meprin β activity at the cell surface is reduced and, consequently, the extent of substrate cleavage is diminished. Our data indicate that this decrease of the surface activity is caused by the internalization and degradation of meprin β.
Fred Armbrust, Kira Bickenbach, Tomas Koudelka, Andreas Tholey, Claus Pietrzik, Christoph Becker-Pauly

1396 related Products with: Phosphorylation of meprin β controls its cell surface abundance and subsequently diminishes ectodomain shedding.

2 Pieces/Box2 Pieces/Box2 Pieces/Box5 x 50 Pieces/case 1 kit500 gm.1 Set1 Set100.00 ug15ml

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#34123813   2021/05/27 To Up

Using Liposomes to Alleviate the Toxicity of Chelerythrine, a Natural PKC Inhibitor, in Treating Non-Small Cell Lung Cancer.

CHE can inhibit the proliferation of lung cancer cells and induce apoptosis. However, despite having toxicity, CHE has not been thoroughly investigated in term of its antitumor effect. The present study evaluated the antitumor effect of CHE on non-small cell lung cancer cell line HCC827.
Jiahui Wang, Yijie Song, Ning Zhang, Ning Li, Congying Liu, Bing Wang

2246 related Products with: Using Liposomes to Alleviate the Toxicity of Chelerythrine, a Natural PKC Inhibitor, in Treating Non-Small Cell Lung Cancer.



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#34113235   2021/05/25 To Up

GPR68 Contributes to Persistent Acidosis-Induced Activation of AGC Kinases and Tyrosine Phosphorylation in Organotypic Hippocampal Slices.

Persistent acidosis occurs in ischemia and multiple neurological diseases. In previous studies, acidic stimulation leads to rapid increase in intracellular calcium in neurons. However, it remains largely unclear how a prolonged acidosis alters neuronal signaling. In our previous study, we found that GPR68-mediated PKC activities are protective against acidosis-induced injury in cortical slices. Here, we first asked whether the same principle holds true in organotypic hippocampal slices. Our data showed that 1-h pH 6 induced PKC phosphorylation in a GPR68-dependent manner. Go6983, a PKC inhibitor worsened acidosis-induced neuronal injury in wild type (WT) but had no effect in GPR68 slices. Next, to gain greater insights into acid signaling in brain tissue, we treated organotypic hippocampal slices with pH 6 for 1-h and performed a kinome profiling analysis by Western blot. Acidosis had little effect on cyclin-dependent kinase (CDK) or casein kinase 2 activity, two members of the CMGC family, or Ataxia telangiectasia mutated (ATM)/ATM and RAD3-related (ATR) activity, but reduced the phosphorylation of MAPK/CDK substrates. In contrast, acidosis induced the activation of CaMKIIα, PKA, and Akt. Besides these serine/threonine kinases, acidosis also induced tyrosine phosphorylation. Since GPR68 is widely expressed in brain neurons, we asked whether GPR68 contributes to acidosis-induced signaling. Deleting GPR68 had no effect on acidosis-induced CaMKII phosphorylation, attenuated that of phospho-Akt and phospho-PKA substrates, while abolishing acidosis-induced tyrosine phosphorylation. These data demonstrate that prolonged acidosis activates a network of signaling cascades, mediated by AGC kinases, CaMKII, and tyrosine kinases. GPR68 is the primary mediator for acidosis-induced activation of PKC and tyrosine phosphorylation, while both GPR68-dependent and -independent mechanisms contribute to the activation of PKA and Akt.
Guokun Zhou, Xiang-Ming Zha

2692 related Products with: GPR68 Contributes to Persistent Acidosis-Induced Activation of AGC Kinases and Tyrosine Phosphorylation in Organotypic Hippocampal Slices.

2 Pieces/Box100ug100ug50 ul2 Pieces/Box2ug100 μg2 Pieces/Box96 assays1 mg2 Pieces/Box1 kit

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#34110637   // To Up

Palmitic acid induces insulin resistance by a mechanism associated with energy metabolism and calcium entry in neuronal cells.

Palmitic acid (PA) is a saturated fatty acid whose high consumption has been largely associated with the development of different metabolic alterations, such as insulin resistance, metabolic syndrome, and type 2 diabetes. Particularly in the brain, insulin signaling disruption has been linked to cognitive decline and is considered a risk factor for Alzheimer's disease. Cumulative evidence has demonstrated the participation of PA in the molecular cascade underlying cellular insulin resistance in peripheral tissues, but its role in the development of neuronal insulin resistance and the mechanisms involved are not fully understood. It has generally been accepted that the brain does not utilize fatty acids as a primary energy source, but recent evidence shows that neurons possess the machinery for fatty acid β-oxidation. However, it is still unclear under what conditions neurons use fatty acids as energy substrates and the implications of their oxidative metabolism in modifying insulin-stimulated effects. In the present work, we have found that neurons differentiated from human neuroblastoma MSN exposed to high but nontoxic concentrations of PA generate ATP through mitochondrial metabolism, which is associated with an increase in the cytosolic Ca and diminished insulin signaling in neurons. These findings reveal a novel mechanism by which saturated fatty acids produce Ca entry and insulin resistance that may play a causal role in increasing neuronal vulnerability associated with metabolic diseases.
Karina Sánchez-Alegría, Carlos Ernesto Bastián-Eugenio, Luis Vaca, Clorinda Arias

2977 related Products with: Palmitic acid induces insulin resistance by a mechanism associated with energy metabolism and calcium entry in neuronal cells.

96 tests96 assays 500 G100ug100.00 ug100ug Lyophilized100ug Lyophilized5mg100ug100ug100ug Lyophilized

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#34110283   2021/06/10 To Up

T cell receptor (TCR) signaling promotes the assembly of RanBP2/RanGAP1-SUMO1/Ubc9 nuclear pore subcomplex via PKC-θ-mediated phosphorylation of RanGAP1.

The nuclear pore complex (NPC) is the sole and selective gateway for nuclear transport and its dysfunction has been associated with many diseases. The metazoan NPC subcomplex RanBP2, which consists of RanBP2 (Nup358), RanGAP1-SUMO1 and Ubc9, regulates the assembly and function of the NPC. The roles of immune signaling in regulation of NPC remain poorly understood. Here, we show that in human and murine T cells, following TCR stimulation, protein kinase C-θ (PKC-θ) directly phosphorylates RanGAP1 to facilitate RanBP2 subcomplex assembly and nuclear import and, thus, the nuclear translocation of AP-1 transcription factor. Mechanistically, TCR stimulation induces the translocation of activated PKC-θ to the NPC, where it interacts with and phosphorylates RanGAP1 on Ser and Ser. RanGAP1 phosphorylation increases its binding affinity for Ubc9, thereby promoting sumoylation of RanGAP1 and, finally, assembly of the RanBP2 subcomplex. Our findings reveal an unexpected role of PKC-θ as a direct regulator of nuclear import and uncover a phosphorylation-dependent sumoylation of RanGAP1, delineating a novel link between TCR signaling and assembly of the RanBP2 NPC subcomplex.
Yujiao He, Zhiguo Yang, Chen-Si Zhao, Zhihui Xiao, Yu Gong, Yun-Yi Li, Yiqi Chen, Yunting Du, Dianying Feng, Amnon Altman, Yingqiu Li

2044 related Products with: T cell receptor (TCR) signaling promotes the assembly of RanBP2/RanGAP1-SUMO1/Ubc9 nuclear pore subcomplex via PKC-θ-mediated phosphorylation of RanGAP1.

2 Pieces/Box100 ug/vial1 mg2 Pieces/Box100.00 ug10000 tests500 tests100.00 ug0.1ml (1mg/ml)1000 tests4

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#34109002   2021/03/22 To Up

Effects of Alzheimer's Disease-Related Proteins on the Chirality of Brain Endothelial Cells.

Cell chirality is an intrinsic cellular property that determines the directionality of cellular polarization along the left-right axis. We recently show that endothelial cell chirality can influence intercellular junction formation and alter trans-endothelial permeability, depending on the uniformity of the chirality of adjacent cells, which suggests a potential role for cell chirality in neurodegenerative diseases with blood-brain barrier (BBB) dysfunctions, such as Alzheimer's disease (AD). In this study, we determined the effects of AD-related proteins amyloid-β (Aβ), tau, and apolipoprotein E4 (ApoE4) on the chiral bias of the endothelial cell component in BBB.
Haokang Zhang, Jie Fan, Zhen Zhao, Chunyu Wang, Leo Q Wan

2438 related Products with: Effects of Alzheimer's Disease-Related Proteins on the Chirality of Brain Endothelial Cells.

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#34108504   2021/06/09 To Up

Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies.

Dietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, β-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from - 11.5 to - 8.5 kcal mol. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents.
Baki Vijaya Bhaskar, Aluru Rammohan, Tirumalasetty Munichandra Babu, Gui Yu Zheng, Weibin Chen, Wudayagiri Rajendra, Grigory V Zyryanov, Wei Gu

2854 related Products with: Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies.

100ug50 mg25 mg1000 TESTS/0.65ml96T100ug10 mg100ug1000 tests50 ug 500 mg200ug

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