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Rho GTPases

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https://www.readbyqxmd.com/read/28102848/statins-in-anthracycline-induced-cardiotoxicity-rac-and-rho-and-the-heartbreakers
#1
REVIEW
Christian Henninger, Gerhard Fritz
Cancer patients receiving anthracycline-based chemotherapy are at risk to develop life-threatening chronic cardiotoxicity with the pathophysiological mechanism of action not fully understood. Besides the most common hypothesis that anthracycline-induced congestive heart failure (CHF) is mainly caused by generation of reactive oxygen species, recent data point to a critical role of topoisomerase II beta (TOP2B), which is a primary target of anthracycline poisoning, in the pathophysiology of CHF. As the use of the only clinically approved cardioprotectant dexrazoxane has been limited by the FDA in 2011, there is an urgent need for alternative cardioprotective measures...
January 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28102564/pkn2-is-essential-for-mouse-embryonic-development-and-proliferation-of-mouse-fibroblasts
#2
Sally Danno, Koji Kubouchi, Mona Mehruba, Manabu Abe, Rie Natsume, Kenji Sakimura, Satoshi Eguchi, Masahiro Oka, Masanori Hirashima, Hiroki Yasuda, Hideyuki Mukai
PKN2, a member of the protein kinase N (PKN) family, has been suggested by in vitro culture cell experiments to bind to Rho/Rac GTPases and contributes to cell-cell contact and cell migration. To unravel the in vivo physiological function of PKN2, we targeted the PKN2 gene. Constitutive disruption of the mouse PKN2 gene resulted in growth retardation and lethality before embryonic day (E) 10.5. PKN2(-/-) embryo did not undergo axial turning and showed insufficient closure of the neural tube. Mouse embryonic fibroblasts (MEFs) derived from PKN2(-/-) embryos at E9...
January 19, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28101920/quantitative-proteomic-analysis-of-hiv-1-tat-induced-dysregulation-in-sh-sy5y-neuroblastoma-cells
#3
Tariq Ganief, Putuma Gqamana, Shaun Garnett, Jackie Hoare, Dan J Stein, John Joska, Nelson Soares, Jonathan M Blackburn
Despite affecting up to 70% of HIV-positivepatients and being the leading cause of dementia in patients under 40 years, the molecular mechanisms involved in the onset of HIV-associated neurocognitive disorders (HAND) are not well understood. To address this, we performed SILAC-based quantitative proteomic analysis on HIV-Tat treated SH-SY5Y neuroblastoma cells. Isolated protein was fractionated by SDS-PAGE and analysed by nLC-MS/MS on an Orbitrap Velos. Using MaxQuant, we identified and quantified 3077 unique protein groups, of which 407 were differentially regulated...
January 19, 2017: Proteomics
https://www.readbyqxmd.com/read/28095620/tools-for-live-imaging-of-active-rho-gtpases-in-xenopus
#4
REVIEW
Rachel E Stephenson, Ann L Miller
Rho family GTPases are signaling molecules that orchestrate cytoskeletal dynamics in a variety of cellular processes. Because they effect localized changes to the cytoskeleton only in their active (GTP-bound) conformation, the ability to monitor the active state of Rho GTPases in space and time is critical for understanding their function. Here, we summarize popular tools used for live imaging of active Rho GTPases, outlining advantages and drawbacks of these approaches. Additionally, we highlight key features of the Xenopus laevis embryo that make it well-suited for epithelial cell biology and discuss how application of Rho activity reporters in the Xenopus laevis embryo led to the discovery of a novel phenomenon, junctional Rho flares...
January 17, 2017: Genesis: the Journal of Genetics and Development
https://www.readbyqxmd.com/read/28092672/bpgap1-spatially-integrates-jnk-erk-signaling-crosstalk-in-oncogenesis
#5
T Jiang, C Q Pan, B C Low
Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28089576/conditional-deletion-of-pejvakin-in-adult-outer-hair-cells-causes-progressive-hearing-loss-in-mice
#6
Suzan L Harris, Marcin Kazmierczak, Tina Pangršič, Prahar Shah, Nadiya Chuchvara, Alonso Barrantes-Freer, Tobias Moser, Martin Schwander
Mutations in the Pejvakin (Pjvk) gene cause autosomal recessive hearing loss DFNB59 with audiological features of auditory neuropathy spectrum disorder (ANSD) or cochlear dysfunction. The precise mechanisms underlying the variable clinical phenotypes of DFNB59 remain unclear. Here, we demonstrate that mice with conditional ablation of the Pjvk gene in all sensory hair cells or only in outer hair cells (OHCs) show similar auditory phenotypes with early-onset profound hearing loss. By contrast, loss of Pjvk in adult OHCs causes a slowly progressive hearing loss associated with OHC degeneration and delayed loss of inner hair cells (IHCs), indicating a primary role for pejvakin in regulating OHC function and survival...
January 9, 2017: Neuroscience
https://www.readbyqxmd.com/read/28089518/transcriptional-pre-patterning-of-drosophila-gastrulation
#7
Bomyi Lim, Michael Levine, Yuji Yamakazi
Gastrulation of the Drosophila embryo is one of the most intensively studied morphogenetic processes in animal development [1-4]. Particular efforts have focused on the formation of the ventral furrow, whereby ∼1,000 presumptive mesoderm cells exhibit coordinated apical constrictions that mediate invagination [5, 6]. Apical constriction depends on a Rho GTPase signaling pathway (T48/Fog) that is deployed by the developmental regulatory genes twist and snail [7-10]. It is thought that coordinate mesoderm constriction depends on high levels of myosin along the ventral midline, although the basis for this localization is uncertain...
January 9, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28088401/pharmacological-rescue-of-adult-hippocampal-neurogenesis-in-a-mouse-model-of-x-linked-intellectual-disability
#8
Manuela Allegra, Cristina Spalletti, Beatrice Vignoli, Stefano Azzimondi, Irene Busti, Pierre Billuart, Marco Canossa, Matteo Caleo
Oligophrenin-1 (OPHN1) is a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID). How loss of function of Ophn1 affects neuronal development is only partly understood. Here we have exploited adult hippocampal neurogenesis to dissect the steps of neuronal differentiation that are affected by Ophn1 deletion. We found that mice lacking Ophn1 display a reduction in the number of newborn neurons in the dentate gyrus. A significant fraction of the Ophn1-deficient newly generated neurons failed to extend an axon towards CA3, and showed an altered density of dendritic protrusions...
January 11, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28078487/the-role-of-the-nox4-derived-ros-mediated-rhoa-rho-kinase-pathway-in-rat-hypertension-induced-by-chronic-intermittent-hypoxia
#9
Wen Lu, Jing Kang, Ke Hu, Si Tang, Xiufang Zhou, Lifang Xu, Yuanyuan Li, Shuhui Yu
BACKGROUND: Obstructive sleep apnea syndrome, which is a risk factor for resistant hypertension, is characterized by chronic intermittent hypoxia (CIH) and is associated with many cardiovascular diseases. CIH elicits systemic oxidative stress and sympathetic hyperactivity, which lead to hypertension. Rho kinases (ROCKs) are considered to be major effectors of the small GTPase RhoA and have been extensively studied in the cardiovascular field. Upregulation of the RhoA/ROCK signaling cascade is observed in various cardiovascular disorders, such as atherosclerosis, pulmonary hypertension, and stroke...
January 11, 2017: Sleep & Breathing, Schlaf & Atmung
https://www.readbyqxmd.com/read/28077617/calcineurin-the-ca2-dependent-phosphatase-regulates-rga2-a-cdc42-gtpase-activating-protein-to-modulate-pheromone-signaling
#10
Nina Ly, Martha S Cyert
Calcineurin, the conserved Ca(2+)/calmodulin-activated phosphatase, is required for viability during prolonged exposure to pheromone, and acts through multiple substrates to down regulate yeast pheromone signaling. Calcineurin regulates Dig2 and Rod1/Art4 to inhibit mating-induced gene expression and activate receptor internalization, respectively. Recent systematic approaches identified Rga2, a GTPase activating protein (GAP) for the Cdc42 Rho-type GTPase, as a calcineurin substrate. Here, we establish a physiological context for this regulation, and show that calcineurin dephosphorylates and positively regulates Rga2 during pheromone signaling...
January 11, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28072828/ggpp-mediated-protein-geranylgeranylation-in-oocyte-is-essential-for-the-establishment-of-oocyte-granulosa-cell-communication-and-primary-secondary-follicle-transition-in-mouse-ovary
#11
Chen Jiang, Fan Diao, Yong-Juan Sang, Na Xu, Rui-Lou Zhu, Xiu-Xing Wang, Zhong Chen, Wei-Wei Tao, Bing Yao, Hai-Xiang Sun, Xing-Xu Huang, Bin Xue, Chao-Jun Li
Folliculogenesis is a progressive and highly regulated process, which is essential to provide ova for later reproductive life, requires the bidirectional communication between the oocyte and granulosa cells. This physical connection-mediated communication conveys not only the signals from the oocyte to granulosa cells that regulate their proliferation but also metabolites from the granulosa cells to the oocyte for biosynthesis. However, the underlying mechanism of establishing this communication is largely unknown...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28072764/antitumour-activity-of-trabectedin-in-myelodysplastic-myeloproliferative-neoplasms
#12
Michela Romano, Matteo Giovanni Della Porta, Anna Gallì, Nicolò Panini, Simonetta Andrea Licandro, Ezia Bello, Ilaria Craparotta, Vittorio Rosti, Elisa Bonetti, Richard Tancredi, Marianna Rossi, Laura Mannarino, Sergio Marchini, Luca Porcu, Carlos M Galmarini, Alberto Zambelli, Marco Zecca, Franco Locatelli, Mario Cazzola, Andrea Biondi, Alessandro Rambaldi, Paola Allavena, Eugenio Erba, Maurizio D'Incalci
BACKGROUND: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN...
January 10, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28065575/multiparametric-analysis-of-cell-shape-demonstrates-that-%C3%AE-pix-directly-couples-yap-activation-to-extracellular-matrix-adhesion
#13
Julia E Sero, Chris Bakal
Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control the activity of mechanosensitive proteins poses a technical challenge, because perturbations that affect cell shape may also affect protein localization indirectly. Here, we present an approach that mitigates confounding effects of cell-shape changes, allowing us to identify direct regulators of YAP localization...
January 2, 2017: Cell Systems
https://www.readbyqxmd.com/read/28065317/preparation-of-centralspindlin-as-an-active-heterotetramer-of-kinesin-and-gtpase-activating-protein-subunits-for-in-vitro-structural-and-functional-assays
#14
M Mishima
Centralspindlin is a crucial regulator of animal cytokinesis, consisting of MKLP1 kinesin-6 and CYK4 Rho-family GTPase activating protein (RhoGAP). As a microtubule-bundling protein, it plays a crucial role in the formation of the central spindle. Through distinct accumulation to the antiparallel microtubule overlaps at the central spindle and the midbody, it recruits various downstream factors to the site of cell division as well as anchors the plasma membrane to maintain the narrow intercellular channels between the daughter cells until their final separation (abscission)...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28064039/roles-of-an-n-terminal-coiled-coil-containing-domain-in-the-localization-and-function-of-bem3-a-rho-gtpase-activating-protein-in-budding-yeast
#15
Wen-Chao Nie, Fei He, Si-Min Yuan, Zhi-Wen Jia, Rui-Rui Wang, Xiang-Dong Gao
GTPase-activating proteins (GAPs) play critical roles in the spatial and temporal control of small GTPases. The budding yeast Bem3 is a GAP for Cdc42, a Rho GTPase crucial for actin and septin organization. Bem3 localizes to the sites of polarized growth. However, the amino acid sequence determinants mediating recruitment of Bem3 to its physiological sites of action and those important for Bem3 function are not clear. Here, we show that Bem3's localization is guided by two distinct targeting regions-the PX-PH-domain-containing TD1 and the coiled-coil-containing TD2...
January 4, 2017: Fungal Genetics and Biology: FG & B
https://www.readbyqxmd.com/read/28062705/novel-p21-activated-kinase-4-pak4-allosteric-modulators-overcome-drug-resistance-and-stemness-in-pancreatic-ductal-adenocarcinoma
#16
Amro Aboukameel, Irfana Muqbil, William Senapedis, Erkan Baloglu, Yosef Landesman, Sharon Shacham, Michael Kauffman, Philip A Philip, Ramzi M Mohammad, Asfar S Azmi
The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and is found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells but not in normal human pancreatic ductal epithelia (HPDE). Gene copy number amplification studies in PDAC patient cohorts confirmed PAK4 amplification making it an attractive therapeutic target in PDAC. We investigated the antitumor activity of novel PAK4 allosteric modulators (PAM) on a panel of PDAC cell lines and chemotherapy-resistant flow-sorted PDAC cancer stem cells (CSC)...
January 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28062165/daboialectin-a-c-type-lectin-from-russell-s-viper-venom-induces-cytoskeletal-damage-and-apoptosis-in-human-lung-cancer-cells-in%C3%A2-vitro
#17
Jigni Pathan, Sukanta Mondal, Angshuman Sarkar, Dibakar Chakrabarty
'Daboialectin', a low molecular weight C-type lectin (18.5 kDa) isolated from Russell's viper venom showed cytotoxic effects on human broncho-alveolar carcinoma derived (A549) cell lines. Daboialectin induced inhibition of A549 cell growth was time and concentration dependent with severe morphological changes by altering the functions of small GTPases such as Rac, Rho and cdc42. ROS induced DNA damage may result in apoptosis by inducing disruption of membrane integrity, blebbing and nuclear disintegration by activating caspases...
January 3, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28051998/prex1-integrates-g-protein-coupled-receptor-and-phosphoinositide-3-kinase-signaling-to-promote-glioblastoma-invasion
#18
Alexander Gont, Manijeh Daneshmand, John Woulfe, Sylvie J Lavictoire, Ian A J Lorimer
A defining feature of the brain cancer glioblastoma is its highly invasive nature. When glioblastoma cells are isolated from patients using serum free conditions, they accurately recapitulate this invasive behaviour in animal models. The Rac subclass of Rho GTPases has been shown to promote invasive behaviour in glioblastoma cells isolated in this manner. However the guanine nucleotide exchange factors responsible for activating Rac in this context have not been characterized previously. PREX1 is a Rac guanine nucleotide exchange factor that is synergistically activated by binding of G protein αγ subunits and the phosphoinositide 3-kinase pathway second messenger phosphatidylinositol 3,4,5 trisphosphate...
December 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/28051168/mechanisms-of-yersinia-yopo-kinase-substrate-specificity
#19
Wei Lin Lee, Pavithra Singaravelu, Sheena Wee, Bo Xue, Khay Chun Ang, Jayantha Gunaratne, Jonathan M Grimes, Kunchithapadam Swaminathan, Robert C Robinson
Yersinia bacteria cause a range of human diseases, including yersiniosis, Far East scarlet-like fever and the plague. Yersiniae modulate and evade host immune defences through injection of Yersinia outer proteins (Yops) into phagocytic cells. One of the Yops, YopO (also known as YpkA) obstructs phagocytosis through disrupting actin filament regulation processes - inhibiting polymerization-promoting signaling through sequestration of Rac/Rho family GTPases and by using monomeric actin as bait to recruit and phosphorylate host actin-regulating proteins...
January 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28042950/ccl24-contributes-to-hcc-malignancy-via-rhob-vegfa-vegfr2-angiogenesis-pathway-and-indicates-poor-prognosis
#20
Lei Jin, Wei-Ren Liu, Meng-Xin Tian, Xi-Fei Jiang, Han Wang, Pei-Yun Zhou, Zhen-Bin Ding, Yuan-Fei Peng, Zhi Dai, Shuang-Jian Qiu, Jian Zhou, Jia Fan, Ying-Hong Shi
CCL24 is one chemotactic factor extensively studied in airway inflammation and colorectal cancer but less studied in hepatocellular carcinoma (HCC) retrospectively. So HCC tissue microarray (TMA) was used to estimate relationship between CCL24 and prognosis, cell experiments were conducted to study its influence for HCC cell biological behavior. CCL24 was injected to nude mice to monitor tumor formation and pulmonary metastasis; qRT-PCR, western blot and Immunohistochemistry were used to explore potential mechanism...
December 22, 2016: Oncotarget
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