المؤلفون: Lili Zhang, Fei Shu

المصدر: Folia Neuropathologica, Vol 62, Iss 1, Pp 47-58 (2023)

مصطلحات موضوعية: alzheimer’s disease, lmtk2, ferroptosis, oxidative stress, apoptotic damage, nrf2/are signalling pathway, Medicine

الوصف: Alzheimer’s disease (AD), the most common contributor to dementia, is a growing global health problem. This study aimed to investigate the role of lemur tyrosine kinase 2 (LMTK2) in AD as well as its relevant mechanism. To establish an in vitro cell model, PC12 cells were challenged with 20 µmol/l Ab 25-35 for 24 h. RT-qPCR and western blot examined LMTK2 mRNA and protein expressions. With the application of CCK-8, TUNEL, iron colorimetric assay kit and DCFH-DA, the viability, apoptosis, Fe 2+ and ROS content in PC12 cells were assessed. Besides, the expressions of oxidative stress-, apoptosis-, ferroptosis- and Nrf2/ARE signalling-related proteins were evaluated with western blot. Moreover, commercial kits examined SOD, MDA and CAT contents. The results manifested that LMTK2 expression was noticeably downregulated in Ab 25-35 -treated PC12 cells. Notably, LMTK2 overexpression exhibited inhibitory effects on oxidative stress, apoptosis and ferroptosis in PC12 cells exposed to Ab 25-35 . The upregulated Nrf2, NQO1 and HO-1 expressions in LMTK2 overexpressed-PC12 cells with Ab 25-35 induction revealed that LMTK2 overexpression could activate the Nrf2/ARE signalling pathway. What is more, a series of cellular experiments further testified that ML385, a specific Nrf2 inhibitor, partly hindered the protective role of LMTK2 overexpression against Ab 25-35 -triggered oxidative stress, apoptosis and ferroptosis in PC12 cells. In conclusion, LMTK2 overexpression alleviated the ferroptosis, oxidant damage and apoptosis in PC12 cells exposed to Ab 25-35 through the activation of the Nrf2/ARE signalling pathway, indicating the potential target of LMTK2 in the treatment of AD.

وصف الملف: electronic resource

العلاقة: https://www.termedia.plTest/LMTK2-inhibits-Ab25-35-elicited-ferroptosis-oxidative-stress-and-apoptotic-damage-in-PC12-cells-through-activating-Nrf2-ARE-signalling-pathway,20,51969,1,1.html; https://doaj.org/toc/1641-4640Test; https://doaj.org/toc/1509-572XTest

الوصول الحر: https://doaj.org/article/9f577c9f68fc446a97f20c562eeec527Test

المؤلفون: de las Fuentes, L., Poveda, A., Franks, P.W., Rotter, J.I.

المصدر: Frontiers in Genetics EpiHealth: Epidemiology for Health EXODIAB: Excellence of Diabetes Research in Sweden eSSENCE: The e-Science Collaboration. 14

مصطلحات موضوعية: cholesterol, educational attainment, genome-wide association study, lipids, meta-analysis, triglycerides, glucose, glutathione, high density lipoprotein cholesterol, interleukin 18, ionotropic receptor, low density lipoprotein cholesterol, ribonucleotide reductase, triacylglycerol, adolescent, adult, aged, Article, brain tissue, BRI3 gene, drug repositioning, electrodermal response, female, FILIP1 gene, FOXP1 gene, gene frequency, gene linkage disequilibrium, genetic analysis, genetic association, genotyping, haplotype, human, LINC00290 gene, lipid metabolism, LMTK2 gene, major clinical study, male, MBOAT4 gene, MYO6 gene, olfactory receptor, protein interaction, proton nuclear magnetic resonance, quality control, SENP6 gene, single nucleotide polymorphism, SKP2 gene, social status, SRGAP3 gene, STIM1 gene, STX4 gene, TMEM167A gene, TMEM30A gene, Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Medicinsk genetik, Medical and Health Sciences, Basic Medicine, Medical Genetics

الوصف: Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects. Copyright © 2023 de las Fuentes

الوصول الحر: https://lup.lub.lu.se/record/23e38fae-9a9e-4c9f-9aa9-108aabeb2322Test
http://dx.doi.org/10.3389/fgene.2023.1235337Test

المؤلفون: Cruz, Daniel Filipe Soares Pereira da

المساهمون: Farinha, Carlos Miguel, Swiatecka-Urban, Agnieszka, Repositório da Universidade de Lisboa

مصطلحات موضوعية: Cystic Fibrosis, LMTK2, TGF-B1, PP1c, signaling pathway, Domínio/Área Científica::Ciências Naturais::Ciências Biológicas

الوصف: Cystic fibrosis (CF), the most common autosomal recessive disease in Caucasians, is a multi-organ disease, affecting the epithelial tissues in the lungs, sweat glands, pancreas, intestine, liver and in the male reproductive tract. CF is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which encodes a Cl- channel expressed at the apical membrane of epithelial cells. Besides the CFTR genotype, other factors influence the heterogeneity of CF lung disease, including environmental and socioeconomic factors and genetic modifiers. Understanding the genetic modifiers will help to unveil their role in disease progression and identify novel therapeutic targets. Transforming Growth Factor (TGF)-β1, besides being a gene modifier of CF lung disease in F508del homozygous patients, has been shown to interfere with the modulators-based functional rescue of F508del-CFTR. Lemur tyrosine kinase 2 (LMTK2), which mediates the inhibitory phosphorylation of CFTR and protein phosphatase 1 catalytic subunit (PP1c), has also been suggested to play a role in CF. This project aims to establish a relation between LMTK2 and the TGF-β1 signaling pathway and understand the role of the interaction in the CF airway. Here, we first observed that TGF-β1 increases LMTK2 abundance at the apical membrane of CFBE41o- cells by increasing Rab11-dependent LMTK2 recycling. Next, we unveiled for the first time that LMTK2 mediates activation of the TGF-β1 signaling pathway. Indeed, TGF-β1 induced the LMTK2-mediated inhibitory phosphorylation of PP1c-Thr320 to promote the activation of its canonical signaling pathway. At last, we increased the knowledge by identifying the LMTK2 networks of genes, proteins, and signaling pathways and elucidated novel molecular and cellular mechanisms of the LMTK2 function in human airway epithelial cells. Our studies may lead to novel therapeutic targets blocking abnormal TGF-β1 signaling, thereby improving the modulators-based functional rescue of CFTR bearing F508del, the most common CF-causing mutation.

وصف الملف: application/pdf

الإتاحة: http://hdl.handle.net/10451/45586Test

المؤلفون: Josh Donovan

مصطلحات موضوعية: Microbiology not elsewhere classified, LMTK2, TGFB

الوصف: Supplemental Data and Figures S1 and S2 for LMTK2 switches on canonical TGF-β1 signaling in human bronchial epithelia

العلاقة: https://figshare.com/articles/figure/Supplemental_Data_and_Figures_S1_and_S2/25245724Test

الإتاحة: https://doi.org/10.6084/m9.figshare.25245724.v1Test
https://figshare.com/articles/figure/Supplemental_Data_and_Figures_S1_and_S2/25245724Test

المؤلفون: Daniel F. Cruz, Nilay Mitash, Fangping Mu, Carlos M. Farinha, Agnieszka Swiatecka-Urban

المصدر: Frontiers in Oncology, Vol 11 (2021)

مصطلحات موضوعية: LMTK2, TGF-β1, RNAseq, gene expression, signaling pathway, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Lemur tyrosine kinase 2 (LMTK2) is a transmembrane Ser/Thr kinase whose role has been increasingly recognized; however, when compared to other kinases, understanding of the LMTK2 networks and biological functions is still limited. Recent data have shown that transforming growth factor (TGF)-β1 plays a role in modulating LMTK2 function by controlling its endocytic trafficking in human bronchial epithelial cells. Here, we aimed to unveil the LMTK2 regulatory network and elucidate how it affects cellular functions and disease pathways in either TGF-β1 dependent or independent manner. To understand how the LMTK2 and TGF-β1 pathways interconnect, we knocked down (KD) LMTK2 using small(si)RNA-mediated silencing in human bronchial epithelial CFBE41o- cells, treated cells with TGF-β1 or vehicle control, and performed differential gene expression analysis by RNA sequencing (RNAseq). In vehicle-treated cells, LMTK2 KD affected expression of 2,506 genes while it affected 4,162 genes after TGF-β1 stimulation. Bioinformatics analysis shows that LMTK2 is involved in diverse cellular functions and disease pathways, such as cell death and survival, cellular development, and cancer susceptibility. In summary, our study increases current knowledge about the LMTK2 network and its intersection with the TGF-β1 signaling pathway. These findings will serve as basis for future exploration of the predicted LMTK2 interactions and signaling pathways.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fonc.2021.596861/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/483787362d444a2ab19af1cdde3b1e8fTest

المؤلفون: Daniel F. Cruz, Nilay Mitash, Carlos M. Farinha, Agnieszka Swiatecka-Urban

المصدر: Frontiers in Cell and Developmental Biology, Vol 8 (2020)

مصطلحات موضوعية: LMTK2, TGF-β1, bronchial epithelial cells, endocytosis, recycling, cystic fibrosis, Biology (General), QH301-705.5

الوصف: The most common disease-causing mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, F508del, leads to cystic fibrosis (CF), by arresting CFTR processing and trafficking to the plasma membrane. The FDA-approved modulators partially restore CFTR function and slow down the progression of CF lung disease by increasing processing and delivery to the plasma membrane and improving activity of F508del-CFTR Cl– channels. However, the modulators do not correct compromised membrane stability of rescued F508del-CFTR. Transforming growth factor (TGF)-β1 is a well-established gene modifier of CF associated with worse lung disease in F508del-homozygous patients, by inhibiting CFTR biogenesis and blocking the functional rescue of F508del-CFTR. Lemur tyrosine kinase 2 (LMTK2) is a transmembrane protein localized at the apical and basolateral membrane domain of human bronchial epithelial cells. Phosphorylation of the apical membrane CFTR by LMTK2 triggers its endocytosis and reduces the abundance of membrane-associated CFTR, impairing the CFTR-mediated Cl– transport. We have previously shown that LMTK2 knockdown improves the pharmacologically rescued F508del-CFTR abundance and function. Thus, reducing the LMTK2 recruitment to the plasma membrane may provide a useful strategy to potentiate the pharmacological rescue of F508del-CFTR. Here, we elucidate the mechanism of LMTK2 recruitment to the apical plasma membrane in polarized CFBE41o- cells. TGF-β1 increased LMTK2 abundance selectively at the apical membrane by accelerating its recycling in Rab11-positive vesicles without affecting LMTK2 mRNA levels, protein biosynthesis, or endocytosis. Our data suggest that controlling TGF-β1 signaling may attenuate recruitment of LMTK2 to the apical membrane thereby improving stability of pharmacologically rescued F508del-CFTR.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fcell.2020.00058/fullTest; https://doaj.org/toc/2296-634XTest

الوصول الحر: https://doaj.org/article/b4f4a7e822844369b7eb42949fe12773Test

المؤلفون: János Bencze, Máté Szarka, Viktor Bencs, Renáta Nóra Szabó, László V. Módis, Dag Aarsland, Tibor Hortobágyi

المصدر: Brain Sciences; Volume 10; Issue 2; Pages: 68

مصطلحات موضوعية: Alzheimer’s disease, LMTK2, neurodegeneration, tau, digital image analysis

الوصف: Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in different brain regions and neuropathological stages of AD is not clear. We performed chromogenic (CHR) LMTK2 and fluorescent phospho-tau/LMTK2 double-labelling (FDL) immunohistochemistry (IHC) on 10–10 postmortem middle frontal gyrus (MFG) and anterior hippocampus (aHPC) samples with early and late neuropathological Braak tau stages of AD. MFG in early stage was our ‘endogenous control’ region as it is not affected by NFTs. Semiquantitative CHR-IHC intensity scoring revealed significantly higher (p < 0.001) LMTK2 values in this group compared to NFT-affected regions. FDL-IHC demonstrated LMTK2 predominance in the endogenous control region, while phospho-tau overburden and decreased LMTK2 immunolabelling were detected in NFT-affected groups (aHPC in early and both regions in late stage). Spearman’s correlation coefficient showed strong negative correlation between phospho-tau/LMTK2 signals within each group. According to our results, LMTK2 expression is inversely proportionate to the extent of NFT pathology, and decreased LMTK2 level is not a general feature in AD brain, rather it is characteristic of the NFT-affected regions.

وصف الملف: application/pdf

العلاقة: Molecular and Cellular Neuroscience; https://dx.doi.org/10.3390/brainsci10020068Test

الإتاحة: https://doi.org/10.3390/brainsci10020068Test

المؤلفون: Bencze, János, Szarka, Máté, Bencs, Viktor, Szabó, Renáta Nóra, Módis, László V., Aarsland, Dag, Hortobágyi, Tibor

المصدر: Bencze , J , Szarka , M , Bencs , V , Szabó , R N , Módis , L V , Aarsland , D & Hortobágyi , T 2020 , ' Lemur tyrosine kinase 2 (LMTK2) level inversely correlates with phospho-Tau in neuropathological stages of alzheimer’s disease ' , Brain Sciences , vol. 10 , no. 2 , 68 . https://doi.org/10.3390/brainsci10020068Test

مصطلحات موضوعية: Digital image analysis, LMTK2, Neurodegeneration, SAlzheimer’s disease, Tau

الوصف: Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in different brain regions and neuropathological stages of AD is not clear. We performed chromogenic (CHR) LMTK2 and fluorescent phospho-tau/LMTK2 double-labelling (FDL) immunohistochemistry (IHC) on 10–10 postmortem middle frontal gyrus (MFG) and anterior hippocampus (aHPC) samples with early and late neuropathological Braak tau stages of AD. MFG in early stage was our ‘endogenous control’ region as it is not affected by NFTs. Semiquantitative CHR-IHC intensity scoring revealed significantly higher (p < 0.001) LMTK2 values in this group compared to NFT-affected regions. FDL- IHC demonstrated LMTK2 predominance in the endogenous control region, while phospho-tau overburden and decreased LMTK2 immunolabelling were detected in NFT-affected groups (aHPC in early and both regions in late stage). Spearman’s correlation coefficient showed strong negative correlation between phospho-tau/LMTK2 signals within each group. According to our results, LMTK2 expression is inversely proportionate to the extent of NFT pathology, and decreased LMTK2 level is not a general feature in AD brain, rather it is characteristic of the NFT-affected regions.

وصف الملف: application/pdf

الإتاحة: https://doi.org/10.3390/brainsci10020068Test
https://kclpure.kcl.ac.uk/portal/en/publications/0a87584b-50c7-4fa4-ae5c-7ae03b7f5323Test
https://kclpure.kcl.ac.uk/ws/files/124308392/brainsci_10_00068.pdfTest
http://www.scopus.com/inward/record.url?scp=85078993240&partnerID=8YFLogxKTest

المؤلفون: János Bencze, Gábor Miklós Mórotz, Woosung Seo, Viktor Bencs, János Kálmán, Christopher Charles John Miller, Tibor Hortobágyi

المصدر: Molecular Brain, Vol 11, Iss 1, Pp 1-9 (2018)

مصطلحات موضوعية: Alzheimer’s disease, Axonal transport, LMTK2, Neurodegeneration, Tau, Neurology. Diseases of the nervous system, RC346-429

الوصف: Abstract Neurodegenerative disorders are frequent, incurable diseases characterised by abnormal protein accumulation and progressive neuronal loss. Despite their growing prevalence, the underlying pathomechanism remains unclear. Lemur tyrosine kinase 2 (LMTK2) is a member of a transmembrane serine/threonine-protein kinase family. Although it was described more than a decade ago, our knowledge on LMTK2’s biological functions is still insufficient. Recent evidence has suggested that LMTK2 is implicated in neurodegeneration. After reviewing the literature, we identified three LMTK2-mediated mechanisms which may contribute to neurodegenerative processes: disrupted axonal transport, tau hyperphosphorylation and enhanced apoptosis. Moreover, LMTK2 gene expression is decreased in an Alzheimer’s disease mouse model. According to these features, LMTK2 might be a promising therapeutic target in near future. However, further investigations are required to clarify the exact biological functions of this unique protein.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s13041-018-0363-xTest; https://doaj.org/toc/1756-6606Test

الوصول الحر: https://doaj.org/article/58e148b32df149afba3042830ea2ec0aTest

المؤلفون: Isha Dey, Neil A. Bradbury

المصدر: Biochemistry and Biophysics Reports, Vol 12, Iss C, Pp 140-150 (2017)

مصطلحات موضوعية: TPA-responsive element, Promoter, LMTK2, AP-1 complex, Phorbol ester, PKC activation, Biology (General), QH301-705.5, Biochemistry, QD415-436

الوصف: Regulatory elements present in the promoter of a gene drive the expression of the gene in response to various stimuli. Lemur Tyrosine Kinase 2 (LMTK2) is a membrane-anchored Serine/Threonine kinase involved in endosomal protein trafficking and androgen signaling amongst other processes. Previous studies have shown this protein to be of therapeutic importance in cystic fibrosis and prostate cancer. However, nothing is known about the endogenous expression of this protein and its regulation. In this study, we analyzed the gene encoding human LMTK2, to look for possible regulatory elements that could affect its expression. Interestingly, the human lmtk2 gene contains a consensus TPA (12- O-Tetradecanoylphorbol-13-acetate)-responsive element (TRE) in the region preceding its start codon. The element with the sequence TGAGTCA modulates LMTK2 expression in response to treatment with TPA, a synthetic Protein Kinase C (PKC) activator. It serves as the binding site for c-Fos, a member of the Activator Protein −1 (AP-1) transcription factor complex, which is transactivated by PKC. We observed that TPA, at low concentrations, increases the promoter activity of LMTK2, which leads to a subsequent increase in the mRNA transcript and protein levels. This modulation occurs through binding of the AP-1 transcription factor complex to the lmtk2 promoter. Thus, our current study has established LMTK2 as a TPA-responsive element-containing gene, which is upregulated downstream of PKC activation. Considering the involvement of LMTK2 in intracellular processes as well as pathological conditions, our findings demonstrate a way to modulate intracellular LMTK2 levels pharmacologically for potentially therapeutic purposes.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2405580817301577Test; https://doaj.org/toc/2405-5808Test

الوصول الحر: https://doaj.org/article/ced8ee8bf2d84b6c975a297ce56b19bcTest