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https://www.readbyqxmd.com/read/28318223/high-throughput-dual-screening-method-for-ras-activities-and-inhibitors
#1
Kari Kopra, Arjan J van Adrichem, Outi M H Salo-Ahen, Juha Peltonen, Krister Wennerberg, Harri J Härmä
Ras GTPases act as "molecular switches", alternating between inactive GDP-bound and active GTP-bound conformation. Ras-oncogenes were discovered over three decades ago, but there are still no effective therapies for Ras-driven cancers. Drug discovery strategies have so far been unsuccessful, due to a lack of suitable screening methodologies and well-defined binding pockets on the Ras proteins. Here, we addressed the former by introducing a homogeneous quenching resonance energy transfer (QRET) technique based screening strategy for Ras interfacial and competitive inhibitors...
March 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28314177/gintonin-attenuates-depressive-like-behaviors-associated-with-alcohol-withdrawal-in-mice
#2
Hyeon-Joong Kim, Sang-Deuk Park, Ra Mi Lee, Byung-Hwan Lee, Sun-Hye Choi, Sung-Hee Hwang, Hyewhon Rhim, Hyoung-Chun Kim, Seung-Yeol Nah
BACKGROUND: Panax ginseng Meyer extracts have been used to improve mood and alleviate symptoms of depression. However, little is known about the extracts' active ingredients and the molecular mechanisms underlying their reported anti-depressive effects. METHODS: Gintonin is an exogenous lysophosphatidic acid (LPA) receptor ligand isolated from P. ginseng. BON cells, an enterochromaffin cell line, and C57BL/6 mice were used to investigate whether gintonin stimulates serotonin release...
March 9, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28304276/scaffold-mediated-gating-of-cdc42-signaling-flux
#3
Péter Rapali, Romain Mitteau, Craig Ronald Braun, Aurèlie Massoni-Laporte, Caner Ünlü, Laure Bataille, Floriane Saint Arramon, Steven P Gygi, Derek McCusker
Scaffold proteins modulate signaling pathway activity spatially and temporally. In budding yeast, the scaffold Bem1 contributes to polarity axis establishment by regulating the GTPase Cdc42. While different models have been proposed for Bem1 function, there is little direct evidence for an underlying mechanism. Here, we find that Bem1 directly augments the Guanine Exchange Factor (GEF) activity of Cdc24. Bem1 also increases GEF phosphorylation by the p21-activated kinase (PAK), Cla4. Phosphorylation abrogates the scaffold-dependent stimulation of GEF activity, rendering Cdc24 insensitive to additional Bem1...
March 17, 2017: ELife
https://www.readbyqxmd.com/read/28304230/modular-regulation-of-rho-family-gtpases-in-development
#4
Marlis Denk-Lobnig, Adam C Martin
Rho family GTPase signaling regulates the actin cytoskeleton and is critical for behaviors that range from the cell to tissue-scale. A theme in Rho GTPase biology is that there are many more regulators, such as guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), than GTPases themselves. Here, we review different, modular cases where GEFs and GAPs function together to elicit precise spatial and temporal control of signaling. We focus on examples from metazoan development, where precise regulation of Rho GTPases is critical for proper tissue form and function...
March 17, 2017: Small GTPases
https://www.readbyqxmd.com/read/28301299/differential-role-for-pak1-and-pak4-during-the-invadopodia-lifecycle
#5
Nicole S Nicholas, Aikaterini Pipili, Michaela S Lesjak, Claire M Wells
PAK1 and PAK4 are members of the p-21 activated kinase family of serine/threonine kinases. PAK1 has previously been implicated in both the formation and disassembly of invasive cell protrusions, termed invadopodia. We recently reported a novel role for PAK4 during invadopodia maturation and confirmed a specific role for PAK1 in invadopodia formation; findings we will review here. Moreover, we found that PAK4 induction of maturation is delivered via interaction with the RhoA regulator PDZRho-GEF. We can now reveal that loss of PAK4 expression leads to changes in invadopodia dynamics...
March 16, 2017: Small GTPases
https://www.readbyqxmd.com/read/28298491/cyk-4-regulates-rac-but-not-rho-during-cytokinesis
#6
Yelena Zhuravlev, Sophia M Hirsch, Shawn N Jordan, Julien Dumont, Mimi Shirasu-Hiza, Julie C Canman
Cytokinesis is driven by constriction of an actomyosin contractile ring that is controlled by Rho family small GTPases. Rho, activated by the Guanine-nucleotide Exchange Factor (GEF) ECT-2, is upstream of both myosin-II activation and diaphanous formin-mediated filamentous actin (f-actin) assembly, which drive ring constriction. The role for Rac and its regulators is more controversial but, based on the finding that Rac inactivation can rescue cytokinesis failure when the GTPase Activating Protein (GAP) CYK-4 is disrupted, Rac activity was proposed to be inhibitory to contractile ring constriction and thus specifically inactivated by CYK-4 at the division plane...
March 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28292916/rab-gtpases-master-regulators-that-establish-the-secretory-and-endocytic-pathways
#7
Suzanne R Pfeffer
Several of the most important discoveries in the field of membrane traffic have come from studies of Rab GTPases by Marino Zerial and Peter Novick and their colleagues. Zerial was the first to discover that Rab GTPases represent identity markers for different membrane-bound compartments, and each Rab organizes a collection of specific effectors into function-specifying membrane microdomains to carry out receptor trafficking. Novick discovered that the order (and thus polarity) of Rab GTPases along the secretory and endocytic pathways are established by their specific, cognate guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which partner with one Rab to regulate the subsequent- and prior-acting Rabs...
March 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28287365/the-gaps-gefs-gdis-and%C3%A2-now-gems-new-kids-on-the-heterotrimeric-g-protein-signaling-block
#8
Pradipta Ghosh, Padmini Rangamani, Irina Kufareva
The canonical process of activation of heterotrimeric G proteins by G protein coupled receptors (GPCRs) is well studied. Recently, a rapidly emerging paradigm has revealed the existence of a new, non-canonical set of cytosolic G protein modulators, guanine exchange modulators (GEMs). Among G proteins regulators, GEMs are uniquely capable of initiating pleiotropic signals: these bifunctional modulators can activate cAMP inhibitory (Gi) proteins and inhibit cAMP-stimulatory (Gs) proteins through a single short evolutionarily conserved module...
March 13, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28287334/regulation-of-rho-gtpase-activity-at-the-leading-edge-of-migrating-cells-by-p190rhogap
#9
Aurélien Bidaud-Meynard, Fabien Binamé, Valérie Lagrée, Violaine Moreau
Cell migration, a key feature of embryonic development, immunity, angiogenesis, and tumor metastasis, is based on the coordinated regulation of actin dynamics and integrin-mediated adhesion. Rho GTPases play a major role in this phenomenon by regulating the onset and maintenance of actin-based protruding structures at cell leading edges (i.e. lamellipodia and filopodia) and contractile structures (i.e., stress fibers) at their trailing edge. While spatio-temporal analysis demonstrated the tight regulation of Rho GTPases at the migration front during cell locomotion, little is known about how the main regulators of Rho GTPase activity, such as GAPs, GEFs and GDIs, play a role in this process...
March 13, 2017: Small GTPases
https://www.readbyqxmd.com/read/28262819/rug3-and-atm-synergistically-regulate-the-alternative-splicing-of-mitochondrial-nad2-and-the-dna-damage-response-in-arabidopsis-thaliana
#10
Chao Su, Hongtao Zhao, Yankun Zhao, Hongtao Ji, Youning Wang, Liya Zhi, Xia Li
The root apical meristem (RAM) determines both RAM activity and the growth of roots. Plant roots are constantly exposed to adverse environmental stresses that can cause DNA damage or cell cycle arrest in the RAM; however, the mechanism linking root meristematic activity and RAM size to the DNA damage response (DDR) is unclear. Here, we demonstrate that a loss of function in RCC1/UVR8/GEF-Like 3 (RUG3) substantially augmented the DDR and produced a cell cycle arrest in the RAM in rug3 mutant, leading to root growth retardation...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28262406/a-novel-inherited-scn1a-mutation-associated-with-gefs-in-benign-and-encephalopathic-epilepsy
#11
Angela C Gauthier, Louis N Manganas, Richard H Mattson
Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant condition often caused by mutations in SCN1A that usually first manifests as childhood simple febrile seizures but may progress to a variety of afebrile generalized seizure types. Here, we describe the case of an 8-year-old boy with a novel SCN1A mutation who developed febrile seizures at 10months of age which eventually advanced to frequent afebrile tonic-clonic seizures. His condition was unresponsive to several antiepileptic drugs and the ketogenic diet, and he experienced gradual cognitive decline...
March 2, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/28260629/uplc-esi-ms-ms-study-of-the-effect-of-green-tea-extract-on-the-oral-bioavailability-of-erlotinib-and-lapatinib-in-rats-potential-risk-of-pharmacokinetic-interaction
#12
Hadir M Maher, Nourah Z Alzoman, Shereen M Shehata, Ashwag O Abahussain
Green tea (GT) is one of the most consumed beverages worldwide. Tyrosine kinase inhibitors (TKIs) belong to the oral targeted therapy that gained much interest in oncology practice, among which are erlotinib (ERL) and lapatinib (LAP). Since green tea polyphenols (GTP) are known to be inhibitors of receptor tyrosine kinases, GTE could likely potentiate the anticancer effect of TKIs, but with a possibility of pharmacokinetic (PK) interaction with co-administered TKIs. In this study, the effect of GTE on the PK of ERL/LAP in rats was studied...
April 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28249939/regulation-of-dennd3-the-exchange-factor-for-the-small-gtpase-rab12-through-an-intramolecular-interaction
#13
Jie Xu, Peter S McPherson
The Rab family of small GTPases function in multiple aspects of cellular membrane trafficking. Proteins bearing a DENN (differentially expressed in normal and neoplastic cells) domain have emerged as the largest family of Rab-activating guanine nucleotide exchange factors (GEFs). Rab12 functions in the initiation of starvation-induced autophagy and our previous work revealed that its activator, DENND3 is phosphorylated and activated upon starvation. However, how the GEF activity of DENND3 towards Rab12 is regulated at the molecular level is still not understood...
March 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28244149/eukaryotic-translation-initiation-factor-2b-beta-eif2b%C3%AE-a-new-class-of-plant-virus-resistance-gene
#14
Shopan Jannat, Haipeng Mou, Lili Zhang, Changtong Zhang, Weiwei Ma, John A Walsh, Zhongyuan Hu, Jinghua Yang, Mingfang Zhang
Recessive resistances to plant viruses in the Potyvirus genus have been found to be based on mutations in the plant eukaryotic translation initiation factors, eIF4E and eIF4G or their isoforms. Here we report that natural, monogenic recessive resistance to the potyvirus Turnip mosaic virus (TuMV) has been found in a number of mustard (Brassica juncea) accessions. Bulked segregant analysis and sequencing of resistant and susceptible plant lines indicated the resistance is controlled by a single recessive gene, recessive TuMV resistance 03 (retr03), an allele of the eukaryotic translation initiation factor 2B-beta (eIF2Bβ)...
February 28, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28228250/stratum-a-homolog-of-the-human-gef-mss4-partnered-with-rab8-controls-the-basal-restriction-of-basement-membrane-proteins-in-epithelial-cells
#15
Olivier Devergne, Gina H Sun, Trudi Schüpbach
The basement membrane (BM), a sheet of extracellular matrix lining the basal side of epithelia, is essential for epithelial cell function and integrity, yet the mechanisms that control the basal restriction of BM proteins are poorly understood. In epithelial cells, a specialized pathway is dedicated to restrict the deposition of BM proteins basally. Here, we report the identification of a factor in this pathway, a homolog of the mammalian guanine nucleotide exchange factor (GEF) Mss4, which we have named Stratum...
February 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28214467/paxillin-a-crossroad-in-pathological-cell-migration
#16
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/28214347/involvement-of-the-guanine-nucleotide-exchange-factor-vav3-in-central-nervous-system-development-and-plasticity
#17
Annika Ulc, Christine Gottschling, Ina Schäfer, David Wegrzyn, Simon van Leeuwen, Veronika Luft, Jacqueline Reinhard, Andreas Faissner
Small GTP-hydrolysing enzymes (GTPases) of the RhoA family play manifold roles in cell biology and are regulated by upstream guanine nucleotide exchange factors (GEFs). Herein, we focus on the GEFs of the Vav subfamily. Vav1 was originally described as a protooncogene of the hematopoietic lineage. The GEFs Vav2 and Vav3 are more broadly expressed in various tissues. In particular, the GEF Vav3 may play important roles in the developing nervous system during the differentiation of neural stem cells into the major lineages, namely neurons, oligodendrocytes and astrocytes...
February 18, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28210903/role-of-exchange-protein-directly-activated-by-camp-epac1-in-breast-cancer-cell-migration-and-apoptosis
#18
Naveen Kumar, Sonal Gupta, Surbhi Dabral, Shailja Singh, Seema Sehrawat
Despite the current progress in cancer research and therapy, breast cancer remains the leading cause of mortality among half a million women worldwide. Migration and invasion of cancer cells are associated with prevalent tumor metastasis as well as high mortality. Extensive studies have powerfully established the role of prototypic second messenger cAMP and its two ubiquitously expressed intracellular cAMP receptors namely the classic protein kinaseA/cAMP-dependent protein kinase (PKA) and the more recently discovered exchange protein directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor (EPAC/cAMP-GEF) in cell migration, cell cycle regulation, and cell death...
February 16, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28202288/tiam1-vav2-rac1-axis-a-tug-of-war-between-islet-function-and-dysfunction
#19
REVIEW
Anjaneyulu Kowluru
Glucose-stimulated insulin secretion [GSIS] from the islet β-cell involves a well-orchestrated interplay between metabolic and cationic events. It is well established that intracellular generation of adenine and guanine nucleotide triphosphates [e.g., ATP and GTP] represents one of the requisite signaling steps in GSIS. The small molecular mass GTP-binding proteins [G-proteins; e.g., Rac1 and Cdc42] have been shown to regulate islet β-cell function including actin cytoskeletal remodeling and fusion of insulin granules with the plasma membrane for GSIS to occur...
February 13, 2017: Biochemical Pharmacology
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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