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PAK1

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https://www.readbyqxmd.com/read/29781585/group-i-paks-support-muscle-regeneration-and-counteract-cancer-associated-muscle-atrophy
#1
Andrea Cerquone Perpetuini, Andrea David Re Cecconi, Michela Chiappa, Giulia Benedetta Martinelli, Claudia Fuoco, Giovanni Desiderio, Luisa Castagnoli, Cesare Gargioli, Rosanna Piccirillo, Gianni Cesareni
BACKGROUND: Skeletal muscle is characterized by an efficient regeneration potential that is often impaired during myopathies. Understanding the molecular players involved in muscle homeostasis and regeneration could help to find new therapies against muscle degenerative disorders. Previous studies revealed that the Ser/Thr kinase p21 protein-activated kinase 1 (Pak1) was specifically down-regulated in the atrophying gastrocnemius of Yoshida hepatoma-bearing rats. In this study, we evaluated the role of group I Paks during cancer-related atrophy and muscle regeneration...
May 21, 2018: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/29780159/modulation-of-store-operated-calcium-entry-and-nascent-adhesion-by-p21-activated-kinase-1
#2
In-Sook Jeon, Hye-Ryun Kim, Eun-Young Shin, Eung-Gook Kim, Heon-Seok Han, Jin-Tae Hong, Hak-Kyo Lee, Ki-Duk Song, Joong-Kook Choi
Calcium mobilization is necessary for cell movement during embryonic development, lymphocyte synapse formation, wound healing, and cancer cell metastasis. Depletion of calcium in the lumen of the endoplasmic reticulum using inositol triphosphate (IP3) or thapsigargin (TG) is known to induce oligomerization and cytoskeleton-mediated translocation of stromal interaction molecule 1 (STIM1) to the plasma membrane, where it interacts with the calcium release-activated calcium channel Orai1 to mediate calcium influx; this process is referred to as store-operated calcium entry (SOCE)...
May 21, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29760342/1-2-3-triazolyl-ester-of-ketorolac-15k-boosting-both-heat-endurance-and-lifespan-of-c-elegans-by-down-regulating-pak1-at-nm-levels
#3
Binh C Nguyen, Sung-A Kim, Seong-Min Won, Sang-Kyu Park, Yoshihiro Uto, Hiroshi Maruta
PAK1 (RAC/CDC42-activated kinase 1) is the major oncogenic/ageing kinase, and its dysfunction extends the healthy lifespan of C. elegans by activating HSP16 gene. 15K is a highly cell-permeable 1,2,3-triazolyl ester of ketorolac that down-regulates both PAK1 and its down-stream COX-2 in R- and S-forms, respectively. 15K is 500-5,000 times more potent than ketorolac, an old pain-killer, inhibiting the growth of cancer cell lines with IC50 ranging 5-24 nM. Scores of natural and synthetic PAK1-blockers have been shown to extend the lifespan of small animals such as C...
2018: Drug Discoveries & Therapeutics
https://www.readbyqxmd.com/read/29734338/rit1-controls-actin-dynamics-via-complex-formation-with-rac1-cdc42-and-pak1
#4
Uta Meyer Zum Büschenfelde, Laura Isabel Brandenstein, Leonie von Elsner, Kristina Flato, Tess Holling, Martin Zenker, Georg Rosenberger, Kerstin Kutsche
RIT1 belongs to the RAS family of small GTPases. Germline and somatic RIT1 mutations have been identified in Noonan syndrome (NS) and cancer, respectively. By using heterologous expression systems and purified recombinant proteins, we identified the p21-activated kinase 1 (PAK1) as novel direct effector of RIT1. We found RIT1 also to directly interact with the RHO GTPases CDC42 and RAC1, both of which are crucial regulators of actin dynamics upstream of PAK1. These interactions are independent of the guanine nucleotide bound to RIT1...
May 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29700602/influence-of-sphingosine-1-phosphate-signaling-on-hcmv-replication-in-human-embryonal-lung-fibroblasts
#5
Anika Zilch, Christian Rien, Cynthia Weigel, Stefanie Huskobla, Brigitte Glück, Katrin Spengler, Andreas Sauerbrei, Regine Heller, Markus Gräler, Andreas Henke
The human cytomegalovirus (HCMV) is a common pathogen, which causes severe or even deadly diseases in immunocompromised patients. In addition, congenital HCMV infection represents a major health concern affecting especially the lung tissue of the susceptible individuals. Antivirals are a useful strategy to treat HCMV-caused diseases. However, all approved drugs target viral proteins but significant toxicity and an increasing resistance against these compounds have been observed. In infected cells, numerous host molecules have been identified to play important roles during HCMV replication...
April 26, 2018: Medical Microbiology and Immunology
https://www.readbyqxmd.com/read/29625277/the-loss-of-p21-activated-kinase-pak1-promotes-atrial-arrhythmic-activity-the-role-of-pak1-in-atrial-arrhythmia
#6
Jaime DeSantiago, Dan J Bare, Disha Varma, R John Solaro, Rishi Arora, Kathrin Banach
BACKGROUND: Atrial fibrillation (AF) is initiated through arrhythmic atrial excitation from outside the sinus node or remodeling of atrial tissue that allows reentry of excitation. Angiotensin II (AngII) has been implicated in initiation and maintenance of AF through changes in Ca2+ handling and production of reactive oxygen species (ROS). OBJECTIVE: We aimed to determine the role of Pak1, a downstream target in the AngII signaling cascade, in atrial electrophysiology and arrhythmia...
April 3, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29616327/whole-exome-sequencing-identifies-key-mutated-genes-in-t790m-wildtype-cmet-unamplified-lung-adenocarcinoma-with-acquired-resistance-to-first-generation-egfr-tyrosine-kinase-inhibitors
#7
Chenguang Li, Hailin Liu, Bin Zhang, Liqun Gong, Yanjun Su, Zhenfa Zhang, Changli Wang
PURPOSE: Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma harboring EGFR-activating mutations will inevitably acquire resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs). EGFR T790M mutation and cMET amplification are common mechanisms. Further study is needed to explore unknown genomic alterations contributing to drug resistance. METHODS: Tumor and blood samples from 69 stage IIIB-IV NSCLC patients defined as acquired resistance to first-generation EGFR TKIs (gefitinib, erlotinib or ecotinib) were collected...
April 3, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29614587/-role-of-rac1-signaling-pathway-of-azathioprine-and-peptidoglycan-in-the-regulation-of-monocyte-macrophage-apoptosis-in-crohn-s-disease
#8
Z Zhou, Y Jing, Y Ran, J Zhao, L Zhou, B M Wang
Objective: To evaluate the changes of macrophages and expression of Rac1 in the inflammatory site of Crohn's disease, and to investigate the effects of 6-thioguanine (6-TG) and peptidoglycan on apoptosis of human peripheral blood monocyte-macrophage by regulating Rac1 signaling pathway. Methods: Ten patients with Crohn's disease and eight healthy controls diagnosed were enrolled at Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital from January 2013 to January 2014. The number of macrophages, apoptosis and expression of Rac1 in the inflammation sites and non-inflammation sites of intestinal mucosa were detected in both patients and controls...
April 1, 2018: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
https://www.readbyqxmd.com/read/29597073/p21-activated-kinase-1-nuclear-activity-and-its-role-during-dna-damage-repair
#9
REVIEW
Eloy Andrés Pérez-Yépez, Héctor Iván Saldívar-Cerón, Olga Villamar-Cruz, Carlos Pérez-Plasencia, Luis Enrique Arias-Romero
p21-activated kinase 1 (PAK1) is a serine/threonine kinase activated by the small GTPases Rac1 and Cdc42. It is located in the chromosome 11q13 and is amplified and/or overexpressed in several human cancer types including 25-30% of breast tumors. This enzyme plays a pivotal role in the control of a number of fundamental cellular processes by phosphorylating its downstream substrates. In addition to its role in the cytoplasm, it is well documented that PAK1 also plays crucial roles in the nucleus participating in mitotic events and gene expression through its association and/or phosphorylation of several transcription factors, transcriptional co-regulators and cell cycle-related proteins, including Aurora kinase A (AURKA), polo-like kinase 1 (PLK1), the forkhead transcription factor (FKHR), estrogen receptor α (ERα), and Snail...
March 21, 2018: DNA Repair
https://www.readbyqxmd.com/read/29556338/elevated-expression-of-mir302-367-in-endothelial-cells-inhibits-developmental-angiogenesis-via-cdc42-ccnd1-mediated-signaling-pathways
#10
Jingjiang Pi, Jie Liu, Tao Zhuang, Lin Zhang, Huimin Sun, Xiaoli Chen, Qian Zhao, Yashu Kuang, Sheng Peng, Xiaohui Zhou, Zuoren Yu, Ting Tao, Brian Tomlinson, Paul Chan, Ying Tian, Huimin Fan, Zhongmin Liu, Xiangjian Zheng, Edward Morrisey, Yuzhen Zhang
Rationale: Angiogenesis is critical for embryonic development and microRNAs fine-tune this process, but the underlying mechanisms remain incompletely understood. Methods: Endothelial cell (EC) specific miR302-367 line was used as gain-of-function and anti-miRs as loss-of-function models to investigate the effects of miR302-367 on developmental angiogenesis with embryonic hindbrain vasculature as an in vivo model and fibrin gel beads and tube formation assay as in vitro models. Cell migration was evaluated by Boyden chamber and scratch wound healing assay and cell proliferation by cell count, MTT assay, Ki67 immunostaining and PI cell cycle analysis...
2018: Theranostics
https://www.readbyqxmd.com/read/29526735/modeling-down-syndrome-with-patient-ipscs-reveals-cellular-and-migration-deficits-of-gabaergic-neurons
#11
Hai-Qin Huo, Zhuang-Yin Qu, Fang Yuan, Lixiang Ma, Lin Yao, Min Xu, Yao Hu, Jing Ji, Anita Bhattacharyya, Su-Chun Zhang, Yan Liu
The brain of Down syndrome (DS) patients exhibits fewer interneurons in the cerebral cortex, but its underlying mechanism remains unknown. By morphometric analysis of cortical interneurons generated from DS and euploid induced pluripotent stem cells (iPSCs), we found that DS GABA neurons are smaller and with fewer neuronal processes. The proportion of calretinin over calbindin GABA neurons is reduced, and the neuronal migration capacity is decreased. Such phenotypes were replicated following transplantation of the DS GABAergic progenitors into the mouse medial septum...
April 10, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29508166/fusobacterium-nucleatum-potentiates-intestinal-tumorigenesis-in-mice-via-a-toll-like-receptor-4-p21-activated-kinase-1-cascade
#12
Yaxin Wu, Jiao Wu, Ting Chen, Qing Li, Wei Peng, Huan Li, Xiaowei Tang, Xiangsheng Fu
BACKGROUND: The underlying pathogenic mechanism of Fusobacterium nucleatum in the carcinogenesis of colorectal cancer has been poorly understood. METHODS: Using C57BL/6-ApcMin/+ mice, we investigated gut microbial structures with F. nucleatum, antibiotics, and Toll-like receptor 4 (TLR4) antagonist TAK-242 treatment. In addition, we measured intestinal tumor formation and the expression of TLR4, p21-activated kinase 1 (PAK1), phosphorylated-PAK1 (p-PAK1), phosphorylated-β-catenin S675 (p-β-catenin S675), and cyclin D1 in mice with different treatments...
May 2018: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29497040/podocyte-specific-rac1-deficiency-ameliorates-podocyte-damage-and-proteinuria-in-stz-induced-diabetic-nephropathy-in-mice
#13
Zhimei Lv, Mengsi Hu, Minghua Fan, Xiaobing Li, Jiangong Lin, Junhui Zhen, Ziyang Wang, Haijun Jin, Rong Wang
Activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) has been implicated in diverse kidney diseases, yet its in vivo significance in diabetic nephropathy (DN) is largely unknown. In the present study, we demonstrated a podocyte-specific Rac1-deficient mouse strain and showed that specific inhibition of Rac1 was able to attenuate diabetic podocyte injury and proteinuria by the blockade of Rac1/PAK1/p38/β-catenin signaling cascade, which reinstated the integrity of podocyte slit diaphragms (SD), rectified the effacement of foot processes (FPs), and prevented the dedifferentiation of podocytes...
March 1, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29487189/integrated-in-vivo-multiomics-analysis-identifies-p21-activated-kinase-signaling-as-a-driver-of-colitis
#14
Jesse Lyons, Douglas K Brubaker, Phaedra C Ghazi, Katherine R Baldwin, Amanda Edwards, Myriam Boukhali, Samantha Dale Strasser, Lucia Suarez-Lopez, Yi-Jang Lin, Vijay Yajnik, Joseph L Kissil, Wilhelm Haas, Douglas A Lauffenburger, Kevin M Haigis
Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that has limited treatment options. To gain insight into the pathogenesis of chronic colonic inflammation (colitis), we performed a multiomics analysis that integrated RNA microarray, total protein mass spectrometry (MS), and phosphoprotein MS measurements from a mouse model of the disease. Because we collected all three types of data from individual samples, we tracked information flow from RNA to protein to phosphoprotein and identified signaling molecules that were coordinately or discordantly regulated and pathways that had complex regulation in vivo...
February 27, 2018: Science Signaling
https://www.readbyqxmd.com/read/29463049/the-anti-cancer-effects-of-frondoside-a
#15
REVIEW
Thomas E Adrian, Peter Collin
Frondoside A is a triterpenoid glycoside from the Atlantic Sea Cucumber, Cucumaria frondosa . Frondoside A has a broad spectrum of anti-cancer effects, including induction of cellular apoptosis, inhibition of cancer cell growth, migration, invasion, formation of metastases, and angiogenesis. In cell lines and animal models studied to date, the anti-cancer effects of the compound are seen in all solid cancers, lymphomas, and leukemias studied to date. These effects appear to be due to potent inhibition of p21-activated kinase 1 (PAK1), which is up-regulated in many cancers...
February 19, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29444419/pak1-kinase-maintains-apical-membrane-identity-in-epithelia
#16
Mario Aguilar-Aragon, Ahmed Elbediwy, Valentina Foglizzo, Georgina C Fletcher, Vivian S W Li, Barry J Thompson
Epithelial cells are polarized along their apical-basal axis by the action of the small GTPase Cdc42, which is known to activate the aPKC kinase at the apical domain. However, loss of aPKC kinase activity was reported to have only mild effects on epithelial cell polarity. Here, we show that Cdc42 also activates a second kinase, Pak1, to specify apical domain identity in Drosophila and mammalian epithelia. aPKC and Pak1 phosphorylate an overlapping set of polarity substrates in kinase assays. Inactivating both aPKC kinase activity and the Pak1 kinase leads to a complete loss of epithelial polarity and morphology, with cells losing markers of apical polarization such as Crumbs, Par3/Bazooka, or ZO-1...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29415725/nischarin-regulates-focal-adhesion-and-invadopodia-formation-in-breast-cancer-cells
#17
Mazvita Maziveyi, Shengli Dong, Somesh Baranwal, Suresh K Alahari
BACKGROUND: During metastasis, tumor cells move through the tracks of extracellular matrix (ECM). Focal adhesions (FAs) are the protein complexes that link the cell cytoskeleton to the ECM and their presence is necessary for cell attachment. The tumor suppressor Nischarin interacts with a number of signaling proteins such as Integrin α5, PAK1, LIMK1, LKB1, and Rac1 to prevent cancer cell migration. Although previous findings have shown that Nischarin exerts this migratory inhibition by interacting with other proteins, the effects of these interactions on the entire FA machinery are unknown...
February 7, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29408512/protein-kinase-c-%C3%AE-stimulates-colorectal-cancer-cell-carcinogenesis-via-pkc-%C3%AE-rac1-pak1-%C3%AE-catenin-signaling-cascade
#18
S M Anisul Islam, Rekha Patel, Mildred Acevedo-Duncan
Colorectal cancer (CRC) is the second most common cancer in the world and death from CRC accounts for 8% of all cancer deaths both in men and women in the United States. CRC is life-threatening disease due to therapy resistant cancerous cells. The exact mechanisms of cell growth, survival, metastasis and inter & intracellular signaling pathways involved in CRC is still a significant challenge. Hence, investigating the signaling pathways that lead to colon carcinogenesis may give insight into the therapeutic target...
April 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29377122/effect-of-l-caldesmon-on-osteoclastogenesis-in-rankl-induced-raw264-7-cells
#19
Ying-Ming Liou, Chu-Lung Chan, Renjian Huang, Chih-Lueh A Wang
Non-muscle caldesmon (l-CaD) is involved in the regulation of actin cytoskeletal remodeling in the podosome formation, but its function in osteoclastogenesis remains to be determined. In this study, RANKL-induced differentiation of RAW264.7 murine macrophages to osteoclast-like cells (OCs) was used as a model to determine the physiological role of l-CaD and its phosphorylation in osteoclastogenesis. Upon RANKL treatment, RAW264.7 cells undergo cell-cell fusion into multinucleate, and TRAP-positive large OCs with a concomitant increase of l-CaD expression...
January 29, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29362425/group-i-paks-mediated-phosphorylation-of-hace1-at-serine-385-regulates-its-oligomerization-state-and-rac1-ubiquitination
#20
Maria I Acosta, Serge Urbach, Anne Doye, Yuen-Wai Ng, Jérôme Boudeau, Amel Mettouchi, Anne Debant, Edward Manser, Orane Visvikis, Emmanuel Lemichez
The regulation of Rac1 by HACE1-mediated ubiquitination and proteasomal degradation is emerging as an essential element in the maintenance of cell homeostasis. However, how the E3 ubiquitin ligase activity of HACE1 is regulated remains undetermined. Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases downstream Rac1 activation by CNF1 toxin from pathogenic E. coli. Moreover, cell treatment with VEGF also promotes Ser-385 phosphorylation of HACE1. We have established in vitro that HACE1 is a direct target of PAK1 kinase activity...
January 23, 2018: Scientific Reports
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