Journal articles: 'PLEKHO1'

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He, Xiaojuan, Jin Liu, Chao Liang, Shaikh Atik Badshah, Kang Zheng, Lei Dang, Baosheng Guo, et al. "Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis." EBioMedicine 41 (March 2019): 538–55. http://dx.doi.org/10.1016/j.ebiom.2019.02.009.

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Liu, Jin, Chao Liang, Baosheng Guo, Xiaohao Wu, Defang Li, Zongkang Zhang, Kang Zheng, et al. "Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging." Aging Cell 16, no. 2 (January 13, 2017): 360–76. http://dx.doi.org/10.1111/acel.12566.

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He, Xiaojuan, Jin Liu, Chao Liang, Shaikh Atik Badshah, Kang Zheng, Lei Dang, Baosheng Guo, et al. "Corrigendum to ‘Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis’ [EBioMedicine 41 (2019) 538–555]." EBioMedicine 52 (February 2020): 102669. http://dx.doi.org/10.1016/j.ebiom.2020.102669.

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Ma, Hong-wei, Min Xie, Ming Sun, Tian-yu Chen, Rong-rong Jin, Tian-shi Ma, Qin-nan Chen, et al. "The pseudogene derived long noncoding RNA DUXAP8 promotes gastric cancer cell proliferation and migration via epigenetically silencing PLEKHO1 expression." Oncotarget 8, no. 32 (August 5, 2016): 52211–24. http://dx.doi.org/10.18632/oncotarget.11075.

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C. Han, Eric, Yu-Chuen Huang, Jane-Ming Lin, Hui-Ju Lin, Jer-Yuarn Wu, Cheng-Chun Lee, and Fuu-Jen Tsai. "Association of the PLEKHO2 and PLEKHH1 gene polymorphisms with type 2 diabetic retinopathy in a Taiwanese population." ScienceAsia 38, no. 4 (2012): 340. http://dx.doi.org/10.2306/scienceasia1513-1874.2012.38.340.

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Xing, Xiangling, Ninni Mu, Xiaotian Yuan, Na Wang, C. Christofer Juhlin, Klas Strååt, Catharina Larsson, and Dawei Xu. "PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma." Cancers 12, no. 8 (July 31, 2020): 2133. http://dx.doi.org/10.3390/cancers12082133.

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Pleckstrin homology domain containing S1 (PLEKHS1) is a poorly characterized factor, although its promoter mutations were identified in human malignancies including thyroid carcinoma (TC). This study was designed to determine PLEKHS1 promoter hotspot mutations in papillary and anaplastic thyroid carcinomas (PTCs and ATCs) and to evaluate if PLEKHS1 expression influences clinical outcome. The PLEKHS1 promoter mutation was observed in 1/93 of PTCs and none of 18 ATCs in our cohort; however, PLEKHS1 expression was aberrantly up-regulated in TCs compared to adjacent non-tumorous thyroid tissues. ATC tumors, an undifferentiated TC, exhibited the highest PLEKHS1 expression. In both TCGA and present cohorts of PTCs, PLEKHS1 gene methylation density was inversely correlated with its mRNA expression and demethylation at the PLEKHS1 locus occurred at two CpGs. Higher PLEKHS1 expression was associated with lymph node and distant metastases, and shorter overall and disease-free survival in our cohort of PTC patients. Importantly, PLEKHS1 over-expression predicted shorter patient survival in PTCs lacking TERT promoter mutations. Cellular experiments showed that PLEKHS1 over-expression enhanced AKT phosphorylation and invasiveness. Collectively, the PLEKHS1 gene demethylation causes its over-expression in PTCs. PLEKHS1 promotes aggressive behavior of TCs possibly by increasing AKT activity, and its over-expression predicts poor patient outcomes.

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Marwaha, Rituraj, Subhash B. Arya, Divya Jagga, Harmeet Kaur, Amit Tuli, and Mahak Sharma. "The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes." Journal of Cell Biology 216, no. 4 (March 21, 2017): 1051–70. http://dx.doi.org/10.1083/jcb.201607085.

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Endocytic, autophagic, and phagocytic vesicles move on microtubule tracks to fuse with lysosomes. Small GTPases, such as Rab7 and Arl8b, recruit their downstream effectors to mediate this transport and fusion. However, the potential cross talk between these two GTPases is unclear. Here, we show that the Rab7 effector PLEKHM1 simultaneously binds Rab7 and Arl8b, bringing about clustering and fusion of late endosomes and lysosomes. We show that the N-terminal RUN domain of PLEKHM1 is necessary and sufficient for interaction with Arl8b and its subsequent localization to lysosomes. Notably, we also demonstrate that Arl8b mediates recruitment of HOPS complex to PLEKHM1-positive vesicle contact sites. Consequently, Arl8b binding to PLEKHM1 is required for its function in delivery and, therefore, degradation of endocytic and autophagic cargo in lysosomes. Finally, we also show that PLEKHM1 competes with SKIP for Arl8b binding, which dictates lysosome positioning. These findings suggest that Arl8b, along with its effectors, orchestrates lysosomal transport and fusion.

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Gill, Emily, Gurimaan Sandhu, Douglas G. Ward, Claire M. Perks, and Richard T. Bryan. "The Sirenic Links between Diabetes, Obesity, and Bladder Cancer." International Journal of Molecular Sciences 22, no. 20 (October 15, 2021): 11150. http://dx.doi.org/10.3390/ijms222011150.

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There is considerable evidence of a positive association between the incidence of type 2 diabetes mellitus (T2DM) and obesity with bladder cancer (BCa), with the link between T2DM and obesity having already been established. There also appear to be potential associations between Pleckstrin homology domain containing S1 (PLEKHS1) and the Insulin-like Growth Factor (IGF) axis. Seven literature searches were carried out to investigate the backgrounds of these potential links. PLEKHS1 is a candidate biomarker in BCa, with mutations that are easily detectable in urine and increased expression seemingly associated with worse disease states. PLEKHS1 has also been implicated as a potential mediator for the onset of T2DM in people with obesity. The substantial evidence of the involvement of IGF in BCa, the role of the IGF axis in obesity and T2DM, and the global prevalence of T2DM and obesity suggest there is scope for investigating the links between these components. Preliminary findings on the relationship between PLEKHS1 and the IGF axis signal possible associations with BCa progression. This indicates that PLEKHS1 plays a role in the pathogenesis of BCa that may be mediated by members of the IGF axis. Further detailed research is needed to establish the relationship between PLEKHS1 and the IGF axis in BCa and determine how these phenomena overlap with T2DM and obesity.

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Tabata, Keisuke, Kohichi Matsunaga, Ayuko Sakane, Takuya Sasaki, Takeshi Noda, and Tamotsu Yoshimori. "Rubicon and PLEKHM1 Negatively Regulate the Endocytic/Autophagic Pathway via a Novel Rab7-binding Domain." Molecular Biology of the Cell 21, no. 23 (December 2010): 4162–72. http://dx.doi.org/10.1091/mbc.e10-06-0495.

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The endocytic and autophagic pathways are involved in the membrane trafficking of exogenous and endogenous materials to lysosomes. However, the mechanisms that regulate these pathways are largely unknown. We previously reported that Rubicon, a Beclin 1–binding protein, negatively regulates both the autophagic and endocytic pathways by unidentified mechanisms. In this study, we performed database searches to identify potential Rubicon homologues that share the common C-terminal domain, termed the RH domain. One of them, PLEKHM1, the causative gene of osteopetrosis, also suppresses endocytic transport but not autophagosome maturation. Rubicon and PLEKHM1 specifically and directly interact with Rab7 via their RH domain, and this interaction is critical for their function. Furthermore, we show that Rubicon but not PLEKHM1 uniquely regulates membrane trafficking via simultaneously binding both Rab7 and PI3-kinase.

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Nishikawa, Masashi, Hidenori Ito, Hidenori Tabata, Hiroshi Ueda, and Koh-ichi Nagata. "Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes." Cells 11, no. 4 (February 16, 2022): 696. http://dx.doi.org/10.3390/cells11040696.

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Homozygosity of the p.Arg204Trp variation in the Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) gene, which encodes a Rho family-specific guanine nucleotide-exchange factor, is responsible for microcephaly with intellectual disability. However, the role of PLEKHG2 during neurodevelopment remains unknown. In this study, we analyzed mouse Plekhg2 function during cortical development, both in vitro and in vivo. The p.Arg200Trp variant in mouse (Plekhg2-RW), which corresponds to the p.Arg204Trp variant in humans, showed decreased guanine nucleotide-exchange activity for Rac1, Rac3, and Cdc42. Acute knockdown of Plekhg2 using in utero electroporation-mediated gene transfer did not affect the migration of excitatory neurons during corticogenesis. On the other hand, silencing Plekhg2 expression delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and p21-activated kinase 1 signaling pathways. This phenotype was rescued by expressing an RNAi-resistant version of wildtype Plekhg2, but not of Plekhg2-RW. Axon pathfinding was also impaired in vitro and in vivo in Plekhg2-deficient cortical neurons. At P14, knockdown of Plekhg2 was observed to cause defects in dendritic spine morphology formation. Collectively, these results strongly suggest that PLEKHG2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEKHG2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders.

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Ben-Zvi, Hadas, Tatiana Rabinski, Rivka Ofir, Smadar Cohen, and Gad D. Vatine. "PLEKHM2 Loss of Function Impairs the Activity of iPSC-Derived Neurons via Regulation of Autophagic Flux." International Journal of Molecular Sciences 23, no. 24 (December 17, 2022): 16092. http://dx.doi.org/10.3390/ijms232416092.

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Pleckstrin Homology And RUN Domain Containing M2 (PLEKHM2) [delAG] mutation causes dilated cardiomyopathy with left ventricular non-compaction (DCM-LVNC), resulting in a premature death of PLEKHM2[delAG] individuals due to heart failure. PLEKHM2 is a factor involved in autophagy, a master regulator of cellular homeostasis, decomposing pathogens, proteins and other cellular components. Autophagy is mainly carried out by the lysosome, containing degradation enzymes, and by the autophagosome, which engulfs substances marked for decomposition. PLEKHM2 promotes lysosomal movement toward the cell periphery. Autophagic dysregulation is associated with neurodegenerative diseases’ pathogenesis. Thus, modulation of autophagy holds considerable potential as a therapeutic target for such disorders. We hypothesized that PLEKHM2 is involved in neuronal development and function, and that mutated PLEKHM2 (PLEKHM2[delAG]) neurons will present impaired functions. Here, we studied PLEKHM2-related abnormalities in induced pluripotent stem cell (iPSC)-derived motor neurons (iMNs) as a neuronal model. PLEKHM2[delAG] iMN cultures had healthy control-like differentiation potential but exhibited reduced autophagic activity. Electrophysiological measurements revealed that PLEKHM2[delAG] iMN cultures displayed delayed functional maturation and more frequent and unsynchronized activity. This was associated with increased size and a more perinuclear lysosome cellular distribution. Thus, our results suggest that PLEKHM2 is involved in the functional development of neurons through the regulation of autophagic flux.

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Zhang, Wei, Liu Li, Piao-Piao Bian, Qiu-Ping Luo, and Zhong-Tang Xiong. "PLEKHA4 Is a Prognostic Biomarker and Correlated with Immune Infiltrates in Glioma." BioMed Research International 2023 (January 17, 2023): 1–21. http://dx.doi.org/10.1155/2023/4504474.

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Objective. Gliomas are the most common and life-threatening intracranial tumors. Immune infiltration of the tumor microenvironment significantly affects tumor prognosis in glioma. Recently, PLEKHA4 was reported to be upregulated in melanoma and closely associated with tumor genesis and development, but its role in glioma is poorly understood. Our aim was to investigate the expression, functional role, and prognostic value of PLEKHA4 in glioma. Methods. The expression levels of PLEKHA4 in 33 types of cancer in the TCGA (The Cancer Genome Atlas) database were collected via the UCSC Xena browser. The clinical samples of glioma patients were downloaded from the TCGA database. Immunohistochemistry was used to verify PLEKHA4 expression in tumor tissues. We assessed the influence of PLEKHA4 on survival of glioma patients by survival module and GEPIA. Then, we downloaded datasets of glioma from TCGA and investigated the correlations between the clinical characteristics and PLEKHA4 expression using logistic regression. Moreover, we used TIMER to explore the collection of PLEKHA4 expression and immune infiltration level in glioma and to analyze cumulative survival in glioma. Gene Set Enrichment Analysis (GSEA) was performed using the TCGA dataset. Results. PLEKHA4 transcript levels were significantly upregulated in multiple cancer types, including gliomas. Moreover, immunohistochemical analysis verified that PLEKHA4 was overexpressed in gliomas compare to the corresponding normal tissues. Univariable survival and multivariate cox analysis show that increased PLEKHA4 expression significantly correlated with age, tumor grade, IDH mutation status, and 1p/19q codel status, and higher PLEKHA4 had shorter OS, DSS, and PFI. Specifically, PLEKHA4 expression level had significant positive correlations with infiltrating levels of B cell, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and DCs in glioma, and upregulation of PLEKHA4 expression was significantly related to immune cell biomarkers and immune checkpoint expression in glioma. In addition, several GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) items associated with immune response, JAK STAT signal pathway, and cell cycle were significantly enriched in the high PLEKHA4 expression phenotype pathway. Conclusions. Our findings proposed that PLEKHA4 was an independent prognostic biomarker and correlated with immune infiltrates in glioma, and targeting PLEKHA4 might improve immunotherapy in glioma. Of course, these findings also need basic experiments and further clinical trials to confirm in the future.

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D'Angelo, Romina, Sandra Aresta, Anne Blangy, Laurence Del Maestro, Daniel Louvard, and Monique Arpin. "Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells." Molecular Biology of the Cell 18, no. 12 (December 2007): 4780–93. http://dx.doi.org/10.1091/mbc.e06-12-1144.

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The mechanisms underlying functional interactions between ERM (ezrin, radixin, moesin) proteins and Rho GTPases are not well understood. Here we characterized the interaction between ezrin and a novel Rho guanine nucleotide exchange factor, PLEKHG6. We show that ezrin recruits PLEKHG6 to the apical pole of epithelial cells where PLEKHG6 induces the formation of microvilli and membrane ruffles. These morphological changes are inhibited by dominant negative forms of RhoG. Indeed, we found that PLEKHG6 activates RhoG and to a much lesser extent Rac1. In addition we show that ezrin forms a complex with PLEKHG6 and RhoG. Furthermore, we detected a ternary complex between ezrin, PLEKHG6, and the RhoG effector ELMO. We demonstrate that PLEKHG6 and ezrin are both required in macropinocytosis. After down-regulation of either PLEKHG6 or ezrin expression, we observed an inhibition of dextran uptake in EGF-stimulated A431 cells. Altogether, our data indicate that ezrin allows the local activation of RhoG at the apical pole of epithelial cells by recruiting upstream and downstream regulators of RhoG and that both PLEKHG6 and ezrin are required for efficient macropinocytosis.

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Huang, Baojun, Weijun Pan, Wenchao Wang, Yijian Wang, Pan Liu, and Wujun Geng. "Overexpression of Pleckstrin Homology Domain-Containing Family A Member 4 Is Correlated with Poor Prognostic Outcomes and Immune Infiltration in Lower-Grade Glioma." Disease Markers 2022 (November 11, 2022): 1–15. http://dx.doi.org/10.1155/2022/1292648.

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Introduction. The global incidence of brain tumors, the most common of which is lower grade glioma (LGG), remains high. Pleckstrin homology domain-containing family A member 4 (PLEKHA4) has been reported to be related to tumor invasion and growth. However, its role and correlation with immunity in LGG remain elusive. Methods. We evaluated the expression pattern, prognostic value, biological functions, and immune effects of PLEKHA4 in LGG. We also analyzed the association between PLEKHA4 levels in different tumors, patient prognosis, and its role in tumor immunity. Depending on the type of research data, we used statistical methods such as Student’s t -tests, Mann–Whitney U tests one-way ANOVA tests Kruskal–Wallis tests Pearson’s or Spearman’s correlation analysis Chi-square and Fisher’s exact tests in this paper. Results and Conclusions. The results revealed that PLEKHA4 levels were markedly elevated in most tumors (such as LGG). High PLEKHA4 levels are associated with poor overall survival (OS), progression-free interval (PFI) rates, and disease-specific survival (DSS) in LGG patients. Cox regression analysis and nomograms showed that PLEKHA4 levels are independent prognostic factors for LGG patients. According to functional enrichment analysis, PLEKHA4 levels in LGG are associated with immune infiltration and immunotherapy. In conclusion, PLEKHA4 is a potential prognostic marker and immunotherapy target for LGG.

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Oria, Victor, Hongyi Zhang, Huifang Zhu, Gang Deng, Christopher Zito, Chetan Rane, Shenqi Zhang, et al. "19. PLEKHA5 REGULATES TUMOR GROWTH IN METASTATIC MELANOMA." Neuro-Oncology Advances 2, Supplement_2 (August 2020): ii3. http://dx.doi.org/10.1093/noajnl/vdaa073.009.

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Abstract Understanding the mechanisms behind melanoma brain metastasis, a disease that continues to portend a poor prognosis, will lead to the identification and development of novel drug targets. We previously identified PLEKHA5, a gene involved in brain development, as a novel molecule implicated in melanoma brain metastasis. Our aim was to further characterize the function of this protein in brain-tropic melanoma. We established stable loss- and gain-of-function cell lines to explore the underlying mechanisms of PLEKHA5-mediated tumor growth. The effect of PLEKHA5 expression silencing on proliferation and tumor growth was assessed using both in vitro systems and xenograft models of brain-tropic melanomas, respectively. The clinical relevance of PLEKHA5 dysregulation in brain metastasis was also investigated in two unique cohorts of melanoma patients with cerebrotropic disease and included analysis of matched cranial and extra-cranial specimens. Knock-down of PLEKHA5 in brain-tropic melanoma cells negatively regulated cell proliferation by inhibiting G1 to S cell cycle transition. This coincided with up-regulation of PDCD4, p21, and p27, as well as the downregulation of pRb protein, involved in the regulation of cell cycle. Conversely, the ectopic re-expression of PLEKHA5 had an inverse effect. Subcutaneous and direct cranial injections of PLEKHA5 knock-down cells in nude mice significantly inhibited tumor growth, while its overexpression upregulated the growth of tumors. This reduction in tumor growth in vivo might be attributed to decreased phosphorylation of Akt (S473) and mTOR (S2448), key mediators for tumor growth and survival. Our results demonstrate the role of PLEKHA5 as a mediator of melanoma brain metastasis. Our findings highlight the significance of PLEKHA5 as a possible regulator of cell cycle transition via crosstalk with the ubiquitin-proteasome and PI3K/AKT/mTOR signaling pathways, driving the proliferation and growth of brain-tropic melanomas. Our studies suggest that PLEKHA5 targeting should be further investigated for melanoma brain metastasis patient population.

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Gupta, Meghana, Elena Kamynina, Samantha Morley, Stacey Chung, Nora Muakkassa, Hong Wang, Shayna Brathwaite, Gaurav Sharma, and Danny Manor. "Plekhg4 Is a Novel Dbl Family Guanine Nucleotide Exchange Factor Protein for Rho Family GTPases." Journal of Biological Chemistry 288, no. 20 (April 9, 2013): 14522–30. http://dx.doi.org/10.1074/jbc.m112.430371.

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Mutations in the PLEKHG4 (puratrophin-1) gene are associated with the heritable neurological disorder autosomal dominant spinocerebellar ataxia. However, the biochemical functions of this gene product have not been described. We report here that expression of Plekhg4 in the murine brain is developmentally regulated, with pronounced expression in the newborn midbrain and brainstem that wanes with age and maximal expression in the cerebellar Purkinje neurons in adulthood. We show that Plekhg4 is subject to ubiquitination and proteasomal degradation, and its steady-state expression levels are regulated by the chaperones Hsc70 and Hsp90 and by the ubiquitin ligase CHIP. On the functional level, we demonstrate that Plekhg4 functions as a bona fide guanine nucleotide exchange factor (GEF) that facilitates activation of the small GTPases Rac1, Cdc42, and RhoA. Overexpression of Plekhg4 in NIH3T3 cells induces rearrangements of the actin cytoskeleton, specifically enhanced formation of lamellopodia and fillopodia. These findings indicate that Plekhg4 is an aggregation-prone member of the Dbl family GEFs and that regulation of GTPase signaling is critical for proper cerebellar function.

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Nguyen, Trang Thi Thu, Wei Sun Park, Byung Ouk Park, Cha Yeon Kim, Yohan Oh, Jin Man Kim, Hana Choi, et al. "PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front." Proceedings of the National Academy of Sciences 113, no. 36 (August 23, 2016): 10091–96. http://dx.doi.org/10.1073/pnas.1604720113.

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Cells migrate by directing Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) activities and by polymerizing actin toward the leading edge of the cell. Previous studies have proposed that this polarization process requires a local positive feedback in the leading edge involving Rac small GTPase and actin polymerization with PI3K likely playing a coordinating role. Here, we show that the pleckstrin homology and RhoGEF domain containing G3 (PLEKHG3) is a PI3K-regulated Rho guanine nucleotide exchange factor (RhoGEF) for Rac1 and Cdc42 that selectively binds to newly polymerized actin at the leading edge of migrating fibroblasts. Optogenetic inactivation of PLEKHG3 showed that PLEKHG3 is indispensable both for inducing and for maintaining cell polarity. By selectively binding to newly polymerized actin, PLEKHG3 promotes local Rac1/Cdc42 activation to induce more local actin polymerization, which in turn promotes the recruitment of more PLEKHG3 to induce and maintain cell front. Thus, autocatalytic reinforcement of PLEKHG3 localization to the leading edge of the cell provides a molecular basis for the proposed positive feedback loop that is required for cell polarization and directed migration.

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Liu, Shuzhen, Guoyan An, Qing Cao, Tong Li, Xinyu Jia, and Lei Lei. "The miR-106b/NR2F2-AS1/PLEKHO2 Axis Regulates Migration and Invasion of Colorectal Cancer through the MAPK Pathway." International Journal of Molecular Sciences 22, no. 11 (May 30, 2021): 5877. http://dx.doi.org/10.3390/ijms22115877.

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Increasing numbers of miRNAs have been observed as oncogenes or tumor suppressors in colorectal cancer (CRC). It was recently reported that hsa-miR-106b-5p (miR-106b) promoted CRC cell migration and invasion. However, there were also studies showing contradictory results. Therefore, in the present study, we further explore the role of miR-106b and its downstream networks in the carcinogenesis of CRC. We observed that the expression of miR-106b is significantly increased in Pan-Cancer and CRC tissues compared with normal tissues from The Cancer Genome Atlas (TCGA) database. Furthermore, we used Transwell, Cell Counting Kit-8, and colony formation assays to clarify that miR-106b promotes the migratory, invasive, and proliferative abilities of CRC cells. For the first time, we systematically screened the target mRNAs and lncRNAs of miR-106b using TCGA database and the bioinformatics algorithms. Dual-luciferase reporter assay confirmed that NR2F2-AS1 and PLEKHO2 are the direct targets of miR-106b. Furthermore, NR2F2-AS1 acts as a competing endogenous RNA (ceRNA) to regulate PLEKHO2 expression by sponging miR-106b. The results of Gene set enrichment analysis (GSEA) and Western blot indicated that they play important roles in CRC progression by regulating MAPK pathway. Thus, miR-106b/NR2F2-AS1/PLEKHO2/MAPK signaling axis may suggest the potential usage in CRC treatment.

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Bridges, Mary C., Joyce Nair-Menon, and Antonis Kourtidis. "2041 The cell-cell adhesion component PLEKHA7 regulates the pro-tumorigenic MIR17HG long non-coding RNA in colon epithelial cells." Journal of Clinical and Translational Science 2, S1 (June 2018): 30. http://dx.doi.org/10.1017/cts.2018.129.

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OBJECTIVES/SPECIFIC AIMS: The goal of this study is to test the hypothesis that the adherens junctions of colon epithelial cells regulate lncRNAs levels and function via the microprocessor and RISC complexes to suppress expression of pro-tumorigenic markers and aberrant cell behavior. METHODS/STUDY POPULATION: To test this hypothesis, we used colon epithelial cancer cell lines. We performed RNA-seq following knockdown of PLEKHA7, a key component of the adherens junctions, to identify changes in lncRNA expression and downstream mRNA levels. We confirmed junctional localization of affected lncRNAs from the RNA-seq and those that we found in our preliminary study by using in situ hybridization (ISH). RESULTS/ANTICIPATED RESULTS: RNA-seq identified junction-associated lncRNAs whose expression levels are regulated by PLEKHA7. The top upregulated lncRNA upon PLEKHA7 depletion was MIR17HG, an oncogenic host transcript of a cluster of miRNAs. These mature miRNAs also co-precipitate with PLEKHA7. PLEKHA7 knockdown results in increased levels of MIR17HG, but only a subset of its hosted miRNAs (miR-19a,b). Notably, miR-19a and mir-19b are highly upregulated in colon cancer. Our data suggest that 2 PLEKHA7-associated miRNAs, miR-203a and miR-372, mediate suppression MIR17HG. Re-expression of PLEKHA7 in aggressive colon cancer cells that lack PLEKHA7 suppressed expression of MIR17HG, as well as anchorage independent growth of these cells. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data point towards a novel mechanism of lncRNA regulation that tethers epithelial tissue integrity with pro-tumorigenic cell transformation. Reducing elevated MIR17HG levels, is a potential therapeutic approach to suppress the tumorigenic behavior of cells that have lost their junctional integrity and homeostasis. identify a network of miRNA-mRNA-lncRNA interactions that could be exploited for further mechanistic studies, as well as for diagnostic and therapeutic purposes in the future.

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Yuan, Tian, Ce Shi, Chen Tian, and M. James You. "The Function and Autophagy Regulation of PLEKHA8 in T Cell Acute Lymphoblastic Leukemia." Blood 136, Supplement 1 (November 5, 2020): 4. http://dx.doi.org/10.1182/blood-2020-138608.

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Introduction:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Over the past 20 years, several oncogenic drivers and crucial signaling pathways have been unraveled in this disease. However, most T-ALL patients are still treated with high dose multiagent chemotherapy due to limited targeted treatment. To further investigate the pathogenesis and develop the new therapeutic targets of T-ALL, we previously developed a mouse genetic model of T-ALL that is deficient forPtentumor suppressor gene. We identified PLEKHA8, a Golgi protein, is highly expressed in thePtenconditional knockout mouse T-ALL. We have verified the high expression of PLEKHA8 in patients' T-ALL samples. PLEKHA8 has the pleckstrin homology (PH) domain binding to phosphatidylinositol 4-monophosphate (PI4P) at the Golgi, is important in lipid metabolism and transport. The Golgi complex regulates the production and delivery of proteins and lipids, and is a site of lipid metabolism needed for autophagy, in particular PI(4)P. We hypothesized that PLEKHA8 affects the cell function and plays a role in the autophagy of human T-ALL via lipid metabolism. Methods:PLEKHA8 was knocked down in T-ALL cell lines using a lentivirus-based vector with shRNAs to assess its effect on cell function. CCK8 assay was employed to detect the cell proliferation. Cell cycle was analyzed using 5-bromo-2'-deoxyuridine (BrdU) and flow cytometry. Autophagy proteins were monitored by western blot. PI(4)P was tested by confocal fluorescence microscopy. Results:T-ALL cells underwent lower cell proliferation and sub-G1 cell accumulation after knocking down PLEKHA8 gene by using shRNA systems. The autophagy marker LC3, Beclin 1 and ATG 5 were markedly increased while P62 decreased after the downregulation PLEKHA8 in T-ALL cells. In addition, PLEKHA8 knocking down in T-ALL cells led to the accumulation of PI(4)P in cytoplasm as observed by confocal fluorescence microscopy. Conclusion:Our data indicate that PLEKHA8 facilitates cell growth in T-ALL cells. Decreased expression of PLEKHA8 inhibits cell proliferation and accumulate sub-G1 phase of T-ALL cells. Decreased PLEKHA8 expression increases the autophagy of T-ALL cells, which could be based on the PI(4)P pathway of autophagy. Our studies provide a new insight into the pathogenesis and potential targeted therapy of T-ALL. Disclosures No relevant conflicts of interest to declare.

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Rouaud, Florian, Francesca Tessaro, Laura Aimaretti, Leonardo Scapozza, and Sandra Citi. "Cooperative binding of the tandem WW domains of PLEKHA7 to PDZD11 promotes conformation-dependent interaction with tetraspanin 33." Journal of Biological Chemistry 295, no. 28 (May 5, 2020): 9299–312. http://dx.doi.org/10.1074/jbc.ra120.012987.

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Pleckstrin homology domain–containing A7 (PLEKHA7) is a cytoplasmic protein at adherens junctions that has been implicated in hypertension, glaucoma, and responses to Staphylococcus aureus α-toxin. Complex formation between PLEKHA7, PDZ domain–containing 11 (PDZD11), tetraspanin 33, and the α-toxin receptor ADAM metallopeptidase domain 10 (ADAM10) promotes junctional clustering of ADAM10 and α-toxin–mediated pore formation. However, how the N-terminal region of PDZD11 interacts with the N-terminal tandem WW domains of PLEKHA7 and how this interaction promotes tetraspanin 33 binding to the WW1 domain is unclear. Here, we used site-directed mutagenesis, glutathione S-transferase pulldown experiments, immunofluorescence, molecular modeling, and docking experiments to characterize the mechanisms driving these interactions. We found that Asp-30 of WW1 and His-75 of WW2 interact through a hydrogen bond and, together with Thr-35 of WW1, form a binding pocket that accommodates a polyproline stretch within the N-terminal PDZD11 region. By strengthening the interactions of the ternary complex, the WW2 domain stabilized the WW1 domain and cooperatively promoted the interaction with PDZD11. Modeling results indicated that, in turn, PDZD11 binding induces a conformational rearrangement, which strengthens the ternary complex, and contributes to enlarging a “hydrophobic hot spot” region on the WW1 domain. The last two lipophilic residues of tetraspanin 33, Trp-283 and Tyr-282, were required for its interaction with PLEKHA7. Docking of the tetraspanin 33 C terminus revealed that it fits into the hydrophobic hot spot region of the accessible surface of WW1. We conclude that communication between the two tandem WW domains of PLEKHA7 and the PLEKHA7–PDZD11 interaction modulate the ligand-binding properties of PLEKHA7.

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Pence, Lindy J., Antonis Kourtidis, Ryan W. Feathers, Mary T. Haddad, Sotiris Sotiriou, Paul A. Decker, Aziza Nassar, Idris T. Ocal, Sejal S. Shah, and Panos Z. Anastasiadis. "PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression." International Journal of Molecular Sciences 22, no. 3 (January 28, 2021): 1275. http://dx.doi.org/10.3390/ijms22031275.

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Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.

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Popov, Lauren M., Caleb D. Marceau, Philipp M. Starkl, Jennifer H. Lumb, Jimit Shah, Diego Guerrera, Rachel L. Cooper, et al. "The adherens junctions control susceptibility toStaphylococcus aureusα-toxin." Proceedings of the National Academy of Sciences 112, no. 46 (October 21, 2015): 14337–42. http://dx.doi.org/10.1073/pnas.1510265112.

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Staphylococcus aureusis both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial α-toxin is essential forS. aureusvirulence in these epithelial diseases. To discover host cellular factors required for α-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known α-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility toS. aureusα-toxin. We find that despite being injured by α-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7−/−mice with methicillin-resistantS. aureusUSA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethalS. aureuspneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential nonessential host target to reduceS. aureusvirulence during epithelial infections.

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Yayici Köken, Özlem, Ülkühan Öztoprak, Vehap Topçu, Büsranur Çavdarli, Çagri Mesut Temucin, Üstün Aydingöz, Özge Dedeoglu Toptas, Hulya Kayilioglu, and Deniz Yuksel. "Expanding the genotype-phenotype spectrum of autosomal recessive Charcot-Marie-Tooth disease: A novel PLEKHG5 gene mutation." Neurology Asia 26, no. 3 (September 2021): 607–12. http://dx.doi.org/10.54029/2021jmr.

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Autosomal recessive intermediate Charcot Marie Tooth (CMT) disease type C is a very rarely-seen neurogenetic disorder. Homozygous or compound heterozygous mutation in the Pleckstrin homology domain-containing family G member 5 (PLEKHG5) gene on chromosome 1p36 was recently reported in patients with CMT. From the first description of the disease to date, almost 40 different variants associated with the PLEKHG5 gene were identified. Here, we present an adolescent girl who was thought initially to be myopathy because of progressive proximal muscle weakness. The electrophysiologic study revealed axonal sensory and motor neuropathy with some demyelinating features. She was diagnosed with autosomal recessive inheritance, intermediate CMT disease type C with a novel homozygous mutation in the PLEKHG5 gene in clinical exome sequencing as c.1600- 2A>G by next-generation sequencing. We describe here the novel mutation in the PLEKHG5 gene and the genotype-phenotype correlation.

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Marques, Rita F., Jan B. Engler, Katrin Küchler, Ross A. Jones, Thomas Lingner, Gabriela Salinas, Thomas H. Gillingwater, Manuel A. Friese, and Kent E. Duncan. "Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis models." Human Molecular Genetics 29, no. 16 (July 7, 2020): 2647–61. http://dx.doi.org/10.1093/hmg/ddaa140.

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Abstract Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease with progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS, and TDP-43 mislocalization in MNs is a key pathological feature of >95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause of disease, specific changes within MNs that trigger disease onset remain unclear. Here, we combined translating ribosome affinity purification (TRAP) with RNA sequencing to identify molecular changes in spinal MNs of TDP-43–driven ALS at motor symptom onset. By comparing the MN translatome of hTDP-43A315T mice to littermate controls and to mice expressing wild type hTDP-43, we identified hundreds of mRNAs that were selectively up- or downregulated in MNs. We validated the deregulated candidates Tex26, Syngr4, and Plekhb1 mRNAs in an independent TRAP experiment. Moreover, by quantitative immunostaining of spinal cord MNs, we found corresponding protein level changes for SYNGR4 and PLEKHB1. We also observed these changes in spinal MNs of an independent ALS mouse model caused by a different patient mutant allele of TDP-43, suggesting that they are general features of TDP-43-driven ALS. Thus, we identified SYNGR4 and PLEKHB1 to be deregulated in MNs at motor symptom onset in TDP-43-driven ALS models. This spatial and temporal pattern suggests that these proteins could be functionally important for driving the transition to the symptomatic phase of the disease.

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McEwan, David G., and Ivan Dikic. "PLEKHM1: Adapting to life at the lysosome." Autophagy 11, no. 4 (April 3, 2015): 720–22. http://dx.doi.org/10.1080/15548627.2015.1034419.

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А.Р., Зарипова,, Надыршина, Д.Д., and Хусаинова, Р.И. "Spectrum and frequency of pathogenic changes in patients with incomplete osteogenesis from the Republic of Bashkortostan." Nauchno-prakticheskii zhurnal «Medicinskaia genetika, no. 9 (September 30, 2022): 41–44. http://dx.doi.org/10.25557/2073-7998.2022.09.41-44.

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Проведен поиск патогенных изменений в целевых генах у 62 пациентов с несовершенным остеогенезом (НО) из 52 семей из Республики Башкортостан с использованием NGS-технологии. В результате проведенного исследования выявлены 29 мутаций в 4 генах (COL1A1, COL1A2, IFITM5, P3H1), ответственных за развитие НО у 42 пациентов из 32 семей. Дополнительно у 7 пациентов с низкотравматичными переломами были найдены гетерозиготные мутации в генах CLCN7, ALOX12B, PLEKHM1, ERCC4, ARSB, PTH1R, TGFB1, которые не участвуют в патогенезе НО. In our study, we searched for pathogenic changes in target genes in 62 patients with osteogenesis imperfecta from 52 families from the Republic of Bashkortostan using NGS technology. The study revealed 29 mutations in 4 genes (COL1A1, COL1A2, IFITM5, P3H1) responsible for the development of OI in 42 patients from 32 families. Additionally, heterozygous mutations in the CLCN7, ALOX12B, PLEKHM1, ERCC4, ARSB, PTH1R, and TGFB1 genes were found in 7 patients with low-traumatic fractures that are not involved in the pathogenesis of OI.

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Beijer, Danique, Kiran Polavarapu, Veeramani Preethish-Kumar, Mainak Bardhan, Maike F. Dohrn, Adriana Rebelo, Stephan Züchner, and Atchayaram Nalini. "Homozygous N-terminal missense variant in PLEKHG5 associated with intermediate CMT: A case report." Journal of Neuromuscular Diseases 9, no. 2 (March 1, 2022): 347–51. http://dx.doi.org/10.3233/jnd-210716.

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Mutations in PLEKHG5, a pleckstrin homology domain containing member of the GEF family, are associated with distal spinal muscular atrophy and intermediate Charcot-Marie-Tooth disease. Here, we describe an isolated case with distal intermediate neuropathy with scapular winging. By whole exome sequencing, we identified the homozygous PLEKHG5 Arg97Gln missense mutation, located in the N-terminal region of the protein. This mutation resides between a zinc-finger motif and a RBD domain, involved in binding rnd3, a RhoA effector protein. We conclude that based on the characteristic phenotype presented by the patient and the supportive genetic findings, the PLEKHG5 mutation is the causative variant.

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Daulagala, Amanda C., and Antonis Kourtidis. "ECM Substrates Impact RNAi Localization at Adherens Junctions of Colon Epithelial Cells." Cells 11, no. 23 (November 23, 2022): 3740. http://dx.doi.org/10.3390/cells11233740.

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The extracellular matrix (ECM) plays crucial roles in tissue homeostasis. Abnormalities in ECM composition are associated with pathological conditions, such as fibrosis and cancer. These ECM alterations are sensed by the epithelium and can influence its behavior through crosstalk with other mechanosensitive complexes, including the adherens junctions (AJs). We have previously shown that the AJs, through their component PLEKHA7, recruit the RNAi machinery to regulate miRNA levels and function. We have particularly shown that the junctional localization of RNAi components is critical for their function. Here, we investigated whether different ECM substrates can influence the junctional localization of RNAi complexes. To do this, we plated colon epithelial Caco2 cells on four key ECM substrates found in the colon under normal or pathogenic conditions, namely laminin, fibronectin, collagen I, and collagen IV, and we examined the subcellular distribution of PLEKHA7, and of the key RNAi components AGO2 and DROSHA. Fibronectin and collagen I negatively impacted the junctional localization of PLEKHA7, AGO2, and DROSHA when compared to laminin. Furthermore, fibronectin, collagen I, and collagen IV disrupted interactions of AGO2 and DROSHA with their essential partners GW182 and DGCR8, respectively, both at AJs and throughout the cell. Combinations of all substrates with fibronectin also negatively impacted junctional localization of PLEKHA7 and AGO2. Additionally, collagen I triggered accumulation of DROSHA at tri-cellular junctions, while both collagen I and collagen IV resulted in DROSHA accumulation at basal areas of cell–cell contact. Altogether, fibronectin and collagens I and IV, which are elevated in the stroma of fibrotic and cancerous tissues, altered localization patterns and disrupted complex formation of PLEKHA7 and RNAi components. Combined with our prior studies showing that apical junctional localization of the PLEKHA7-RNAi complex is critical for regulating tumor-suppressing miRNAs, this work points to a yet unstudied mechanism that could contribute to epithelial cell transformation.

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Rawet-Slobodkin, Moran, and Zvulun Elazar. "PLEKHM1: A Multiprotein Adaptor for the Endolysosomal System." Molecular Cell 57, no. 1 (January 2015): 1–3. http://dx.doi.org/10.1016/j.molcel.2014.12.022.

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McEwan, David G., Benjamin Richter, Beatrice Claudi, Christoph Wigge, Philipp Wild, Hesso Farhan, Kieran McGourty, et al. "PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection." Cell Host & Microbe 17, no. 1 (January 2015): 58–71. http://dx.doi.org/10.1016/j.chom.2014.11.011.

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Saini, Arushi Gahlot, Naveen Sankhyan, and Sameer Vyas. "PLEKHG2-associated neurological disorder." BMJ Case Reports 14, no. 7 (July 2021): e244206. http://dx.doi.org/10.1136/bcr-2021-244206.

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Yamada, Kenichiro, Noriko Nomura, Arisa Yamano, Yasukazu Yamada, and Nobuaki Wakamatsu. "Identification and characterization of splicing variants of PLEKHA5 (Plekha5) during brain development." Gene 492, no. 1 (January 2012): 270–75. http://dx.doi.org/10.1016/j.gene.2011.10.018.

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Le goux, C., D. Damotte, S. Vacher, N. Barry-delongchamps, M. Sibony, B. Terris, M. Zerbib, I. Bièche, and G. Pignot. "Valeur pronostique de PLEKHS1 dans la carcinogénèse urothéliale vésicale." Progrès en Urologie 26, no. 13 (November 2016): 766. http://dx.doi.org/10.1016/j.purol.2016.07.197.

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Zhang, Pengfei, Chenchen Zhou, Cheng Lu, Wenfei Li, Wei Li, Bin Jing, Wenxia Chen, et al. "PLEKHO2 is essential for M-CSF-dependent macrophage survival." Cellular Signalling 37 (September 2017): 115–22. http://dx.doi.org/10.1016/j.cellsig.2017.06.006.

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NILL, FLORIAN. "A CONSTRUCTIVE QUANTUM FIELD THEORETIC APPROACH TO CHERN-SIMONS THEORY." International Journal of Modern Physics B 06, no. 11n12 (June 1992): 2159–98. http://dx.doi.org/10.1142/s0217979292001080.

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Chern-Simons theory is formulated quantum field theoretically in terms of string operators, which are localized on finite non-selfintersecting paths in the zero-time plane R2. It is shown how the Weyl algebra approach to the abelian Chern-Simons theory leads to a bundle theoretic construction of these ‘Chern-Simons string operators’. To proceed to the non-abelian case topological Chern-Simons theory is considered as a specific model of a more general theory describing the quantum kinematics of coloured framed Plek ton s inR2. This theory allows the construction of string operators as pair-creation operators, mapping n-Plekton states into (n+2)-Plekton states. Link invariants are obtained as vacuum correlation functions of string operators and obey a natural version of reflection positivity. The vacuum sector of such a purely kinematical Plekton theory may be recovered from the link invariants by Osterwalder-Schrader reconstruction. To make the theory work one needs the structures of a ribbon graph category, for which the representations of a quasi-triangular quasi-Hopf algebra may serve as a specific realization.

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Belekhova, Svetlana Georgievna, and Yury Sergeevich Astakhov. "The role of genetically determined factors in age-related macular degeneration pathogenesis." Ophthalmology journal 8, no. 4 (December 15, 2015): 30–39. http://dx.doi.org/10.17816/ov2015430-39.

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The article presents a review of studies dedicated to the role of genetic factors in age-related macular degeneration (AMD) pathogenesis. The polymorphisms of Y402H gene of the complement factor Н, HTRA1, ARMS2/LOC387715, and PLEKHA1 increase the risk of AMD development. More detailed description is done also for other genes, involved into this disease, which were identified so far. Possible schemes of influence of mutations in these genes on AMD development and progression

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Gray, Kathryn J., Vesela P. Kovacheva, Hooman Mirzakhani, Andrew C. Bjonnes, Berta Almoguera, Andrew T. DeWan, Elizabeth W. Triche, et al. "Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1." Hypertension 72, no. 2 (August 2018): 408–16. http://dx.doi.org/10.1161/hypertensionaha.117.10688.

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Radhi, Ohood Aqeed. "The Role of PLEKHM1 in Salmonella enterica sv. Typhimurium infection." Indian Journal of Forensic Medicine & Toxicology 13, no. 4 (2019): 1036. http://dx.doi.org/10.5958/0973-9130.2019.00436.5.

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Shi, Haihong, Rongrong Zhu, Nan Hu, Jian Shi, Junfang Zhang, Linjuan Jiang, Hong Jiang, and Huaijin Guan. "An Extensive Replication Study on Three New Susceptibility Loci of Primary Angle Closure Glaucoma in Han Chinese: Jiangsu Eye Study." Journal of Ophthalmology 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/641596.

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Genome-wide association study (GWAS) analysis identified three new susceptibility loci for PACG. In this study, we aimed to investigate whether these three loci in PLEKHA7, COL11A1, and PCMTD1-ST18 are associated with PAC and ocular biometric characteristics, such as axial length (AL), anterior chamber depth (ACD), and diopter of spherical power (DS). The study was a part of the Jiangsu Eye Study. The samples were collected from 232 PAC subjects and 306 controls from a population-based prevalence survey conducted in Funing County of Jiangsu, China. The single nucleotide polymorphisms (SNPs) of rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 in PCMTD1-ST18 were genotyped by TaqMan-MGB probe using the RT-PCR system. None of the three polymorphisms showed differences in the distribution of genotypes and allele frequencies between the PAC group and the control group. No significant association was determined between the 3 SNPs and AL, ACD, or DS of PAC subjects. We concluded that even though PLEKHA7 rs11024102, COL11A1 rs3753841, and PCMTD1-ST18 rs1015213 are associated with PACG, those sequence variations are not associated with PAC in a Han Chinese population. Our results also did not support a significant role for these three SNPs in ocular biometry such as AL, ACD, and DS.

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Traylor, Matthew, Daniel J. Tozer, Iain D. Croall, Danuta M. Lisiecka Ford, Abiodun Olubunmi Olorunda, Giorgio Boncoraglio, Martin Dichgans, et al. "Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226)." Neurology 92, no. 8 (January 18, 2019): e749-e757. http://dx.doi.org/10.1212/wnl.0000000000006952.

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ObjectiveTo identify novel genetic associations with white matter hyperintensities (WMH).MethodsWe performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels.ResultsWe identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013]; p = 1.6 × 10−8), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10−9). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03–1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00–1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; β [SE] = 0.106 [0.016]; p = 1.2 × 10−11 and rs7596872; β [SE] = 0.143 [0.021]; p = 3.4 × 10−12). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability.ConclusionsGenetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.

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Witwicka, Hanna, Hong Jia, Artem Kutikov, Pablo Reyes-Gutierrez, Xiangdong Li, and Paul R. Odgren. "TRAFD1 (FLN29) Interacts with Plekhm1 and Regulates Osteoclast Acidification and Resorption." PLOS ONE 10, no. 5 (May 19, 2015): e0127537. http://dx.doi.org/10.1371/journal.pone.0127537.

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Paschoud, Serge, Lionel Jond, Diego Guerrera, and Sandra Citi. "PLEKHA7 modulates epithelial tight junction barrier function." Tissue Barriers 2, no. 2 (April 2014): e28755. http://dx.doi.org/10.4161/tisb.28755.

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Zhang, Hongyi, Huifang Zhu, Gang Deng, Christopher R. Zito, Victor O. Oria, Chetan K. Rane, Shenqi Zhang, et al. "PLEKHA5 regulates tumor growth in metastatic melanoma." Cancer 126, no. 5 (November 26, 2019): 1016–30. http://dx.doi.org/10.1002/cncr.32611.

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McEwan, David G., Doris Popovic, Andrea Gubas, Seigo Terawaki, Hironori Suzuki, Daniela Stadel, Fraser P. Coxon, et al. "PLEKHM1 Regulates Autophagosome-Lysosome Fusion through HOPS Complex and LC3/GABARAP Proteins." Molecular Cell 57, no. 1 (January 2015): 39–54. http://dx.doi.org/10.1016/j.molcel.2014.11.006.

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Klink, Aaron. "Hidden Holiness â By Michael Plekon." Religious Studies Review 35, no. 4 (December 2009): 250. http://dx.doi.org/10.1111/j.1748-0922.2009.01381_46.x.

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Kourtidis, Antonis, Brian Necela, Wan-Hsin Lin, Ruifeng Lu, Ryan W. Feathers, Yan W. Asmann, E. Aubrey Thompson, and Panos Z. Anastasiadis. "Cadherin complexes recruit mRNAs and RISC to regulate epithelial cell signaling." Journal of Cell Biology 216, no. 10 (September 6, 2017): 3073–85. http://dx.doi.org/10.1083/jcb.201612125.

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Cumulative evidence demonstrates that most RNAs exhibit specific subcellular distribution. However, the mechanisms regulating this phenomenon and its functional consequences are still under investigation. Here, we reveal that cadherin complexes at the apical zonula adherens (ZA) of epithelial adherens junctions recruit the core components of the RNA-induced silencing complex (RISC) Ago2, GW182, and PABPC1, as well as a set of 522 messenger RNAs (mRNAs) and 28 mature microRNAs (miRNAs or miRs), via PLEKHA7. Top canonical pathways represented by these mRNAs include Wnt/β-catenin, TGF-β, and stem cell signaling. We specifically demonstrate the presence and silencing of MYC, JUN, and SOX2 mRNAs by miR-24 and miR-200c at the ZA. PLEKHA7 knockdown dissociates RISC from the ZA, decreases loading of the ZA-associated mRNAs and miRNAs to Ago2, and results in a corresponding increase of MYC, JUN, and SOX2 protein expression. The present work reveals a mechanism that directly links junction integrity to the silencing of a set of mRNAs that critically affect epithelial homeostasis.

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Huybrechts, Yentl, and Wim Van Hul. "Osteopetrosis associated with PLEKHM1 and SNX10 genes, both involved in osteoclast vesicular trafficking." Bone 164 (November 2022): 116520. http://dx.doi.org/10.1016/j.bone.2022.116520.

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Coxon, F. P., A. Taylor, L. Van Wesenbeeck, and W. Van Hul. "Plekhm1 is involved in trafficking of cathepsin K-containing endosomal vesicles in osteoclasts." Bone 44 (June 2009): S248. http://dx.doi.org/10.1016/j.bone.2009.03.120.

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Lee, Jiyeon, Ji-Hyun Hwang, Harim Chun, Wonjin Woo, Sekyung Oh, Jungmin Choi, and Lark Kyun Kim. "PLEKHA8P1 Promotes Tumor Progression and Indicates Poor Prognosis of Liver Cancer." International Journal of Molecular Sciences 22, no. 14 (July 16, 2021): 7614. http://dx.doi.org/10.3390/ijms22147614.

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Hepatocellular carcinoma (HCC) records the second-lowest 5-year survival rate despite the avalanche of research into diagnosis and therapy. One of the major obstacles in treatment is chemoresistance to drugs such as 5-fluorouracil (5-FU), making identification and elucidation of chemoresistance regulators highly valuable. As the regulatory landscape grows to encompass non-coding genes such as long non-coding RNAs (lncRNAs), a relatively new class of lncRNA has emerged in the form of pseudogene-derived lncRNAs. Through bioinformatics analyses of the TCGA LIHC dataset, we have systematically identified pseudogenes of prognostic value. Initial experimental validation of selected pseudogene-derived lncRNA (PLEKHA8P1) and its parental gene (PLEKHA8), a well-studied transport protein in Golgi complex recently implicated as an oncogene in both colorectal and liver cancer, indicates that the pseudogene/parental gene pair promotes tumor progression and that their dysregulated expression levels affect 5-FU-induced chemoresistance in human HCC cell line FT3-7. Our study has thus confirmed cancer-related functions of PLEKHA8, and laid the groundwork for identification and validation of oncogenic pseudogene-derived lncRNA that shows potential as a novel therapeutic target in circumventing chemoresistance induced by 5-FU.

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Journal articles on the topic 'PLEKHO1'

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