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Rac1 RhoA

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https://www.readbyqxmd.com/read/28528353/adrenomedullin-ameliorates-podocyte-injury-induced-by-puromycin-aminonucleoside-in-vitro-and-in-vivo-through-modulation-of-rho-gtpases
#1
Nan Dong, Lixia Meng, Ruqun Xue, Meng Yu, Zhonghua Zhao, Xueguang Liu
PURPOSE: Podocyte injury is a key event in proteinuric kidney disease and eventually glomerular scarring. While adrenomedullin (AM), a potent vasodilatory peptide, has been reported to confer renoprotection in several experimental models of kidney diseases, its effect on injured podocytes and the related mechanism is still largely unknown. METHODS: Employing Western blotting analysis, immunoprecipitation and immunofluorescence, we investigated the effects of AM on the expressions of podocyte cytoskeletal proteins and Rho-family small GTPases (Rho GTPases) in puromycin aminonucleoside (PAN)-induced podocyte injury, both in cultured podocytes and in PAN nephrosis rats...
May 20, 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28502648/control-of-astrocyte-morphology-by-rho-gtpases
#2
REVIEW
Andre Zeug, Franziska E Müller, Stefanie Anders, Michel K Herde, Daniel Minge, Evgeni Ponimaskin, Christian Henneberger
Astrocytes modulate and support neuronal and synapse function via numerous mechanisms that often rely on diffusion of signalling molecules, ions or metabolites through extracellular space. As a consequence, the spatial arrangement and the distance between astrocyte processes and neuronal structures is of functional importance. Likewise, changes of astrocyte structure will affect the ability of astrocytes to interact with neurons. In contrast to neurons, where rapid morphology changes are critically involved in many aspects of physiological brain function, a role of astrocyte restructuring in brain physiology is only beginning to emerge...
May 11, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28465528/wnt5a-induces-ror1-to-associate-with-14-3-3%C3%AE-for-enhanced-chemotaxis-and-proliferation-of-chronic-lymphocytic-leukemia-cells
#3
J Yu, L Chen, Y Chen, K Hasan, E M Ghia, L Zhang, R Wu, L Z Rassenti, G F Widhopf, Z Shen, S P Briggs, T J Kipps
Wnt5a can activate Rho GTPases in chronic lymphocytic leukemia cells by inducing the recruitment of ARHGEF2 to ROR1. Mass spectrometry on immune-precipitates of Wnt5a-activated ROR1 identified 14-3-3ζ, which was confirmed by co-immunoprecipitation. The capacity of Wnt5a to induce ROR1 to complex with 14-3-3ζ could be blocked in CLL cells treated with cirmtuzumab, a humanized mAb targeting ROR1. Silencing 14-3-3ζ via siRNA impaired the capacity of Wnt5a to: (1) induce recruitment of ARHGEF2 to ROR1, (2) enhance in vitro exchange activity of ARHGEF2, and (3) induce activation of RhoA and Rac1 in CLL cells...
May 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28423648/polyisoprenylated-cysteinyl-amide-inhibitors-disrupt-actin-cytoskeleton-organization-induce-cell-rounding-and-block-migration-of-non-small-cell-lung-cancer
#4
Elizabeth Ntantie, Jerrine Fletcher, Felix Amissah, Olufisayo O Salako, Augustine T Nkembo, Rosemary A Poku, Francis O Ikpatt, Nazarius S Lamango
The malignant potential of Non-Small Cell Lung Cancer (NSCLC) is dependent on cellular processes that promote metastasis. F-actin organization is central to cell migration, invasion, adhesion and angiogenesis, processes involved in metastasis. F-actin remodeling is enhanced by the overexpression and/or hyper-activation of some members of the Rho family of small GTPases. Therefore, agents that mitigate hyperactive Rho proteins may be relevant for controlling metastasis. We previously reported the role of polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential inhibitors of cancers with hyperactive small GTPases...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28410221/discovery-and-characterization-of-small-molecule-rac1-inhibitors
#5
Jamie L Arnst, Ashley L Hein, Margaret A Taylor, Nick Y Palermo, Jacob I Contreras, Yogesh A Sonawane, Andrew O Wahl, Michel M Ouellette, Amarnath Natarajan, Ying Yan
Aberrant activation of Rho GTPase Rac1 has been observed in various tumor types, including pancreatic cancer. Rac1 activates multiple signaling pathways that lead to uncontrolled proliferation, invasion and metastasis. Thus, inhibition of Rac1 activity is a viable therapeutic strategy for proliferative disorders such as cancer. Here we identified small molecule inhibitors that target the nucleotide-binding site of Rac1 through in silico screening. Follow up in vitro studies demonstrated that two compounds blocked active Rac1 from binding to its effector PAK1...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28409572/-fret-based-biosensors-in-cell-migration-research
#6
Sławomir Lasota, Zbigniew Baster, Tomasz Witko, Eliza Zimoląg, Jolanta Sroka, Zenon Rajfur, Zbigniew Madeja
Cell migration is a complicated process, which is crucial for functioning of multicellular organisms. Multiple signalling pathways are deeply involved in the precise control of consecutive cell migration stages based on remodelling of the actin cytoskeleton. Small Rho GTPases (RhoA, Rac1 and Cdc42) as well as multiple protein and lipid kinases, calcium ions and mechanosensors are crucial components in this process. Exploration of those complicated correlations is possible with constant advancement of fluorescence microscopy...
2017: Postepy Biochemii
https://www.readbyqxmd.com/read/28386321/acid-fibroblast-growth-factor-preserves-blood-brain-barrier-integrity-by-activating-the-pi3k-akt-rac1-pathway-and-inhibiting-rhoa-following-traumatic-brain-injury
#7
Fenzan Wu, Zaifeng Chen, Chonghui Tang, Jinjing Zhang, Li Cheng, Hongxia Zuo, Hongyu Zhang, Daqing Chen, Liping Xiang, Jian Xiao, Xiaokun Li, Xinlong Xu, Xiaojie Wei
The blood-brain barrier (BBB) plays important roles in the recovery of traumatic brain injury (TBI) which is a major factor contributing to cerebral edema. Acid fibroblast growth factor (aFGF) contributes to maintain vascular integrity and restores nerve function. However, whether aFGF protects BBB following TBI remains unknown. The purpose of this study was to determine whether exogenous aFGF preserves BBB integrity by activating the PI3K-Akt-Rac1 pathway and inhibiting RhoA after TBI. BBB permeability was assessed using evans blue dye and fluorescein isothiocyanate dextran fluorescence...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28376111/coordinated-balance-of-rac1-and-rhoa-plays-key-roles-in-determining-phagocytic-appetite
#8
Sang-Yeob Kim, Soyoun Kim, Dong-Jun Bae, Seung-Yoon Park, Ga-Young Lee, Gyeong-Min Park, In-San Kim
The removal of unwanted or damaged cells by phagocytes is achieved via a finely regulated cleaning process called efferocytosis. To characterize the mechanisms through which phagocytes control the intake of apoptotic cells, we investigated how the phagocyte's appetite for engulfed cells may be coordinated by RhoA and Rac1 in the phagocytic cup. We used FRET biosensors to visualize the spatiotemporal dynamics of Rho-family GTPases, and found that RhoA, which is known to be downregulated during phagocytosis, was transiently upregulated at the phagocytic cup immediately prior to ingestion...
2017: PloS One
https://www.readbyqxmd.com/read/28371345/the-prostate-metastasis-suppressor-gene-ndrg1-differentially-regulates-cell-motility-and-invasion
#9
Anup Sharma, Janet Mendonca, James Ying, Hea-Soo Kim, James E Verdone, Jelani C Zarif, Michael Carducci, Hans Hammers, Kenneth J Pienta, Sushant Kachhap
Experimental and clinical evidence suggests that N-myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1-deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1-deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1-deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility...
April 2, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28363850/di-n-butyl-phthalate-exposure-negatively-influences-structural-and-functional-neuroplasticity-via-rho-gtpase-signaling-pathways
#10
Yuemin Ding, Lingchao Lu, Chengkai Xuan, Jiajv Han, Shumin Ye, Tingting Cao, Weibo Chen, Aiqing Li, Xiong Zhang
Di-n-butyl phthalate (DBP) has been reported to cause disruptions in hippocampal plasticity, but its specific mechanism has not yet been ascertained. In this research, a mouse model of chronic DBP exposure was generated by intragastric administration of DBP (10, 50, or 250°mg/kg/d) for 5 weeks. Chronic exposure to high concentrations of DBP (250°mg/kg/d) induced a spatial learning deficit in the Morris water maze in male mice. By determining the activity of Rho-GTPase signaling pathways in the hippocampal tissues, we found that DBP exposure inhibited the activity of Rac1/PAK1/LIMK1 but activated RhoA/ROCK/LIMK2 signaling and eventually suppressed cofilin activity by phosphorylation...
March 28, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28344327/mevalonate-cascade-inhibition-by-simvastatin-induces-the-intrinsic-apoptosis-pathway-via-depletion-of-isoprenoids-in-tumor-cells
#11
Javad Alizadeh, Amir A Zeki, Nima Mirzaei, Sandipan Tewary, Adel Rezaei Moghadam, Aleksandra Glogowska, Pandian Nagakannan, Eftekhar Eftekharpour, Emilia Wiechec, Joseph W Gordon, Fred Y Xu, Jared T Field, Ken Y Yoneda, Nicholas J Kenyon, Mohammad Hashemi, Grant M Hatch, Sabine Hombach-Klonisch, Thomas Klonisch, Saeid Ghavami
The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway...
March 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28339090/inhibition-of-farnesyl-pyrophosphate-synthase-attenuates-high-glucose%C3%A2-induced-vascular-smooth-muscle-cells-proliferation
#12
Guo-Ping Chen, Xiao-Qin Zhang, Tao Wu, Jie Han, Dan Ye
The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis accelerated by hyperglycemia. Our previous studies found that farnesyl pyrophosphate synthase (FPPS, EC 2.5.1.10), an essential enzyme in the mevalonate pathway, was upregulated in aorta media from diabetic mice along with the process of atherosclerosis. However, the exact role of FPPS in high glucose‑induced proliferation of VSMCs is largely unclear. In our study, we found that alendronate (an FPPS inhibitor) attenuated diabetic accelerated atherosclerosis in vivo and suppressed high glucose‑induced VSMCs proliferation in vitro...
May 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28301477/fragility-of-foot-process-morphology-in-kidney-podocytes-arises-from-chaotic-spatial-propagation-of-cytoskeletal-instability
#13
Cibele V Falkenberg, Evren U Azeloglu, Mark Stothers, Thomas J Deerinck, Yibang Chen, John C He, Mark H Ellisman, James C Hone, Ravi Iyengar, Leslie M Loew
Kidney podocytes' function depends on fingerlike projections (foot processes) that interdigitate with those from neighboring cells to form the glomerular filtration barrier. The integrity of the barrier depends on spatial control of dynamics of actin cytoskeleton in the foot processes. We determined how imbalances in regulation of actin cytoskeletal dynamics could result in pathological morphology. We obtained 3-D electron microscopy images of podocytes and used quantitative features to build dynamical models to investigate how regulation of actin dynamics within foot processes controls local morphology...
March 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28289332/pi3k%C3%AE-isoform-dependent-activation-of-rhoa-regulates-wnt5a-induced-osteosarcoma-cell-migration
#14
Ailiang Zhang, Ting Yan, Kun Wang, Zhihui Huang, Jinbo Liu
BACKGROUND: We have reported that the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway mediated Wnt5a-induced osteosarcoma cell migration. However, the signaling pathways regulating Wnt5a/PI3K/Akt-mediated cell migration remains poorly defined in osteosarcoma cells. METHODS: We evaluated the activations of RhoA, Rac1 and Cdc42 in osteosarcoma MG-63 and U2OS cells with small G-protein activation assay. Boyden chamber assays were used to confirm the migration of cells transfected indicated constructs or siRNA specific against RhoA...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28287327/mechanism-of-cell-intrinsic-adaptation-to-adams-oliver-syndrome-gene-dock6-disruption-highlights-ubiquitin-like-modifier-isg15-as-a-regulator-of-rho-gtpases
#15
Berati Cerikan, Elmar Schiebel
DOCK6 is a RAC1/CDC42 guanine nucleotide exchange factor, however, little is known about its function and sub-cellular localization. DOCK6 regulates the balance between RAC1 and RHOA activity during cell adhesion and is important for CDC42-dependent mitotic chromosome alignment. Surprisingly, a cell intrinsic adaptation mechanism compensates for errors in these DOCK6 functions that arise as a consequence of prolonged DOCK6 depletion or complete removal in DOCK6 knockout cells. Down-regulation of the ubiquitin-like modifier ISG15 accounts for this adaptation...
February 23, 2017: Small GTPases
https://www.readbyqxmd.com/read/28238662/coordination-by-cdc42-of-actin-contractility-and-adhesion-for-melanoblast-movement-in-mouse-skin
#16
Emma F Woodham, Nikki R Paul, Benjamin Tyrrell, Heather J Spence, Karthic Swaminathan, Michelle R Scribner, Evangelos Giampazolias, Ann Hedley, William Clark, Frieda Kage, Daniel J Marston, Klaus M Hahn, Stephen W G Tait, Lionel Larue, Cord H Brakebusch, Robert H Insall, Laura M Machesky
The individual molecular pathways downstream of Cdc42, Rac, and Rho GTPases are well documented, but we know surprisingly little about how these pathways are coordinated when cells move in a complex environment in vivo. In the developing embryo, melanoblasts originating from the neural crest must traverse the dermis to reach the epidermis of the skin and hair follicles. We previously established that Rac1 signals via Scar/WAVE and Arp2/3 to effect pseudopod extension and migration of melanoblasts in skin...
March 6, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28235899/dual-targeting-of-mesenchymal-and-amoeboid-motility-hinders-metastatic-behavior
#17
Brandon C Jones, Laura C Kelley, Yuriy V Loskutov, Kristina M Marinak, Varvara K Kozyreva, Matthew B Smolkin, Elena N Pugacheva
Commonly upregulated in human cancers, the scaffolding protein NEDD9/HEF1 is a known regulator of mesenchymal migration and cancer cell plasticity. However, the functional role of NEDD9 as a regulator of different migration/invasion modes in the context of breast cancer metastasis is currently unknown. Here, it is reported that NEDD9 is necessary for both mesenchymal and amoeboid individual cell migration/invasion in triple-negative breast cancer (TNBC). NEDD9 deficiency results in acquisition of the amoeboid morphology, but severely limits all types of cell motility...
February 24, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28231640/mind-the-gap-mechanisms-regulating-the-endothelial-barrier
#18
REVIEW
M Y Radeva, J Waschke
The endothelial barrier consists of intercellular contacts localized in the cleft between endothelial cells, which is covered by the glycocalyx in a sievelike manner. Both types of barrier-forming junctions, i.e. the adherens junction (AJ) serving mechanical anchorage and mechanotransduction and the tight junction (TJ) sealing the intercellular space to limit paracellular permeability, are tethered to the actin cytoskeleton. Under resting conditions, the endothelium thereby builds a selective layer controlling the exchange of fluid and solutes with the surrounding tissue...
February 23, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28214467/paxillin-a-crossroad-in-pathological-cell-migration
#19
REVIEW
Ana María López-Colomé, Irene Lee-Rivera, Regina Benavides-Hidalgo, Edith López
Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and signaling molecules involved in cell movement and migration, when phosphorylated on specific Tyr and Ser residues. Upon integrin engagement with extracellular matrix, paxillin is phosphorylated at Tyr31, Tyr118, Ser188, and Ser190, activating numerous signaling cascades which promote cell migration, indicating that the regulation of adhesion dynamics is under the control of a complex display of signaling mechanisms...
February 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28196833/characterization-of-the-activation-of-small-gtpases-by-their-gefs-on-membranes-using-artificial-membrane-tethering
#20
François Peurois, Simon Veyron, Yann Ferrandez, Ilham Ladid, Sarah Benabdi, Mahel Zeghouf, Gérald Peyroche, Jacqueline Cherfils
Attachment of active, GTP-bound small GTPases to membranes by post-translational lipid modifications is pivotal for their ability to process and propagate information in cells. However, generating and manipulating lipidated GTPases has remained difficult, which has limited our quantitative understanding of their activation by GEFs and their termination by GAPs. Here we replaced the lipid modification by a histidine tag in eleven full-length, human small GTPases belonging to the Arf, Rho and Rab families, which allowed to tether them to nickel-lipid containing membranes and characterize the kinetics of their activation by GEFs...
February 14, 2017: Biochemical Journal
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