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GTPase AND "GTP levels"

Alessandro Contini, Nicola Ferri, Raffaella Bucci, Maria Giovanna Lupo, Emanuela Erba, Maria Luisa Gelmi, Sara Pellegrino
Rac1 GTPase interaction with guanine nucleotide exchange factor Tiam1 is involved in several cancer types and cardiovascular diseases. Although small molecules interfering with their protein-protein interaction (PPI) were identified and studied, the ability of small peptides and peptide mimics acting as Rac1/Tiam1 PPI inhibitors has not been yet explored. Using computational alanine scanning (CAS), the "hot" interfacial residues have been determined allowing the design of a small library of putative PPI inhibitors...
November 27, 2017: Biopolymers
Xiaoling Bao, Heng Liu, Xing Liu, Ke Ruan, Yonghui Zhang, Zhiyong Zhang, Qi Hu, Ying Liu, Saima Akram, Jiahai Zhang, Qingguo Gong, Wenwen Wang, Xiao Yuan, Jian Li, Lingli Zhao, Zhen Dou, Ruijun Tian, Xuebiao Yao, Jihui Wu, Yunyu Shi
Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation. The Ran GTPase plays a key role in mitotic spindle assembly. However, how the generation of a chemical gradient of Ran-GTP at the spindle is coupled to mitotic post-translational modifications has never been characterized. Here, we solved the complex structure of Ran with the nucleotide release factor Mog1 and delineated a novel mitosis-specific acetylation-regulated Ran-Mog1 interaction during chromosome segregation...
October 6, 2017: Journal of Molecular Cell Biology
Nisha Bte Mohd Rafiq, Zi Zhao Lieu, Tingting Jiang, Cheng-Han Yu, Paul Matsudaira, Gareth E Jones, Alexander D Bershadsky
Podosomes represent a class of integrin-mediated cell-matrix adhesions formed by migrating and matrix-degrading cells. We demonstrate that in macrophage-like THP1 cells and fibroblasts stimulated to produce podosomes, down-regulation of the G-protein ARF1 or the ARF1 guanine nucleotide exchange factor, ARNO, by small, interfering RNA or pharmacological inhibitors led to striking podosome elimination. Concomitantly, treatments inducing podosome formation increased the level of guanosine triphosphate (GTP)-bound ARF1...
January 2, 2017: Journal of Cell Biology
Nadia Jaber, Noor Mohd-Naim, Ziqing Wang, Jennifer L DeLeon, Seong Kim, Hua Zhong, Namratha Sheshadri, Zhixun Dou, Aimee L Edinger, Guangwei Du, Vania M M Braga, Wei-Xing Zong
The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI(3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells to delineate whether Vps34 has additional roles in endocytic trafficking. In Vps34-/- mouse embryonic fibroblasts (MEFs), transferrin recycling and EEA1 membrane localization were unaffected despite elevated Rab5-GTP levels. Strikingly, a large increase in Rab7-GTP levels, an accumulation of enlarged late endosomes, and decreased EGFR degradation were observed in Vps34-deficient cells...
December 1, 2016: Journal of Cell Science
Alexander E Urban, Erin O Quick, Kaylie P Miller, Jennifer Krcmery, Hans-Georg Simon
Upon vessel injury, platelets become activated and rapidly reorganize their actin cytoskeleton to adhere to the site of endothelial damage, triggering the formation of a fibrin-rich plug to prevent further blood loss. Inactivation of Pdlim7 provides the new perspective that regulation of actin cytoskeletal changes in platelets is dependent on the encoded PDZ-LIM protein. Loss-of-function of Pdlim7 triggers hypercoagulopathy and causes significant perinatal lethality in mice. Our in vivo and in vitro studies reveal that Pdlim7 is dynamically distributed along actin fibers, and lack of Pdlim7 leads to a marked inability to rearrange the actin cytoskeleton...
2016: PloS One
Simone Kälin, Dominik P Buser, Martin Spiess
Rab GTPases act as organizers of protein networks defining identities and functions of organelles of the endocytic and secretory pathways. Various modes of coordination between different Rabs drive the timely maturation and conversion of membranes. Endosomal Rab5 has been known as the prime example for self-activation via a feedback loop recruiting Rabaptin5, which is complexed with the Rab5 exchange factor Rabex5, and couples to Rab4-GTP. Among other effectors, Rab5 also recruits the Mon1/SAND1-Ccz1 complex that both activates Rab7 and dissociates Rabex5 for Rab5-to-Rab7 conversion of early-to-late endosomes...
2016: Small GTPases
Kollu N Rao, Linjing Li, Wei Zhang, Richard S Brush, Raju V S Rajala, Hemant Khanna
It is unclear how genes, such as RPGR (retinitis pigmentosa guanine triphosphatase regulator) that are expressed in both rods and cones, cause variable disease pathogenesis. Using transcriptomic analysis, we show that loss of RPGR in a rod-dominant mouse retina (Rpgr(ko)) results in predominant alterations in genes involved in actin cytoskeletal dynamics, prior to onset of degeneration. We validated these findings and found an increase in activated RhoA-GTP levels and polymerized F-actin in the Rpgr(ko) mouse retina...
April 1, 2016: Human Molecular Genetics
Pavol Cekan, Keisuke Hasegawa, Yu Pan, Emily Tubman, David Odde, Jin-Qiu Chen, Michelle A Herrmann, Sheetal Kumar, Petr Kalab
The coordination of cell cycle progression with the repair of DNA damage supports the genomic integrity of dividing cells. The function of many factors involved in DNA damage response (DDR) and the cell cycle depends on their Ran GTPase-regulated nuclear-cytoplasmic transport (NCT). The loading of Ran with GTP, which is mediated by RCC1, the guanine nucleotide exchange factor for Ran, is critical for NCT activity. However, the role of RCC1 or Ran⋅GTP in promoting cell proliferation or DDR is not clear. We show that RCC1 overexpression in normal cells increased cellular Ran⋅GTP levels and accelerated the cell cycle and DNA damage repair...
April 15, 2016: Molecular Biology of the Cell
Zoltan Nagy, Kieran Wynne, Alexander von Kriegsheim, Stepan Gambaryan, Albert Smolenski
Endothelial cells release prostacyclin (PGI2) and nitric oxide (NO) to inhibit platelet functions. PGI2 and NO effects are mediated by cyclic nucleotides, cAMP- and cGMP-dependent protein kinases (PKA, PKG), and largely unknown PKA and PKG substrate proteins. The small G-protein Rac1 plays a key role in platelets and was suggested to be a target of cyclic nucleotide signaling. We confirm that PKA and PKG activation reduces Rac1-GTP levels. Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets...
December 11, 2015: Journal of Biological Chemistry
Sriganesh B Sharma, John Michael Ruppert
MicroRNAs (miRs) have been causally implicated in the progression and development of a wide variety of cancers. miRs modulate the activity of key cell signaling networks by regulating the translation of pathway component proteins. Thus, the pharmacological targeting of miRs that regulate cancer cell signaling networks, either by promoting (using miR-supplementation) or by suppressing (using antisense oligonucleotide-based strategies) miR activity is an area of intense research. The RAS-extracellular signal regulated kinase (ERK) pathway represents a major miR-regulated signaling network that endows cells with some of the classical hallmarks of cancer, and is often inappropriately activated in malignancies by somatic genetic alteration through point mutation or alteration of gene copy number...
September 2015: Drug Development Research
Dipannita Dutta, Julie G Donaldson
Clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE) co-exist in most cells but little is known about their communication and coordination. Here we show that when CME was inhibited, endocytosis by CIE continued but endosomal trafficking of CIE cargo proteins was altered. CIE cargo proteins that normally traffic directly into Arf6-associated tubules after internalization and avoid degradation (CD44, CD98 and CD147) now trafficked to lysosomes and were degraded. The endosomal tubules were also absent and Arf6-GTP levels were elevated...
September 2015: Traffic
B L Slomiany, A Slomiany
A small GTPase, Rac1, is recognized as an important modulator of the inflammatory responses to bacterial lipopolysaccharide (LPS) by affecting the processes of phospholipase C activation. The activation of Rac1 involves the exchange of GDP for GTP and is catalyzed by the guanine nucleotide exchange factors (GEFs). Here, we report on the gastric mucosal GEF, Dock180, activation in response to H. pylori PS, and the hormone, ghrelin. We show that stimulation of gastric mucosal cells with the LPS leads to up-regulation in Dock180 phosphorylation on Tyr and Ser that is accompanied by a massive rise in Rac1-GTP level, while the effect of ghrelin, manifested by a drop in Dock180 phosphorylation on Ser, is associated with a decrease in Rac1-GTP formation...
June 2015: Inflammopharmacology
Yaoyao Qi, Zhimin Liang, Zonghua Wang, Guodong Lu, Guangpu Li
Rab5 targets to early endosomes and is a master regulator of early endosome fusion and endocytosis in all eukaryotic cells. Like other GTPases, Rab5 functions as a molecular switch by alternating between GTP-bound and GDP-bound forms, with the former being biologically active via interactions with multiple effector proteins. Thus the Rab5-GTP level in the cell reflects Rab5 activity in promoting endosome fusion and endocytosis and is indicative of cellular endocytic activity. In this chapter, we describe a Rab5 activity assay by using GST fusion proteins with the Rab5 effectors such as Rabaptin-5, Rabenosyn-5, and EEA1 that specifically bind to GTP-bound Rab5...
2015: Methods in Molecular Biology
Houbin Zhang, Christin Hanke-Gogokhia, Li Jiang, Xiaobo Li, Pu Wang, Cecilia D Gerstner, Jeanne M Frederick, Zhenglin Yang, Wolfgang Baehr
The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Δ (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The Rp2h(-/-) mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease...
March 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Georgina A Cardama, Nazareno Gonzalez, Matias Ciarlantini, Lucia Gandolfi Donadío, María Julieta Comin, Daniel F Alonso, Pablo Lorenzano Menna, Daniel E Gomez
Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels...
2014: OncoTargets and Therapy
Arkadi Manukyan, Kirsten Ludwig, Sergio Sanchez-Manchinelly, Sarah J Parsons, P Todd Stukenberg
The cytokinetic furrow is organized by the RhoA GTPase, which recruits actin and myosin II to the furrow and drives contractility. Here, we show that the RhoA GTPase-activting protein (GAP) p190RhoGAP-A (also known as ARHGAP35) has a role in cytokinesis and is involved in regulating levels of RhoA-GTP and contractility. Cells depleted of p190RhoGAP-A accumulate high levels of RhoA-GTP and markers of high RhoA activity in the furrow, resulting in failure of the cytokinetic furrow to progress to abscission. The loss of p190RhoGAP-A can be rescued by a low dose of the myosin II inhibitor blebbistatin, suggesting that cells fail cytokinesis because they have too much myosin activity...
January 1, 2015: Journal of Cell Science
Elizabeth J Gray, Evangelia Petsalaki, D Andrew James, Richard D Bagshaw, Melissa M Stacey, Oliver Rocks, Anne-Claude Gingras, Tony Pawson
SH2D5 is a mammalian-specific, uncharacterized adaptor-like protein that contains an N-terminal phosphotyrosine-binding domain and a C-terminal Src homology 2 (SH2) domain. We show that SH2D5 is highly enriched in adult mouse brain, particularly in Purkinjie cells in the cerebellum and the cornu ammonis of the hippocampus. Despite harboring two potential phosphotyrosine (Tyr(P)) recognition domains, SH2D5 binds minimally to Tyr(P) ligands, consistent with the absence of a conserved Tyr(P)-binding arginine residue in the SH2 domain...
December 19, 2014: Journal of Biological Chemistry
Pil Jung Kang, Mid Eum Lee, Hay-Oak Park
Cell polarization occurs along a single axis that is generally determined by a spatial cue, yet the underlying mechanism is poorly understood. Using biochemical assays and live-cell imaging, we show that cell polarization to a proper growth site requires activation of Cdc42 by Bud3 in haploid budding yeast. Bud3 catalyzes the release of guanosine diphosphate (GDP) from Cdc42 and elevates intracellular Cdc42-guanosine triphosphate (GTP) levels in cells with inactive Cdc24, which has as of yet been the sole GDP-GTP exchange factor for Cdc42...
July 7, 2014: Journal of Cell Biology
Jixian Luo, Koa Hosoki, Attila Bacsi, Zsolt Radak, Muralidhar L Hegde, Sanjiv Sur, Tapas K Hazra, Allan R Brasier, Xueqing Ba, Istvan Boldogh
Reactive oxygen species (ROS) are activators of cell signaling and modify cellular molecules, including DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the prominent lesions in oxidatively damaged DNA, whose accumulation is causally linked to various diseases and aging processes, whereas its etiological relevance is unclear. 8-OxoG is repaired by the 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated DNA base excision repair (BER) pathway. OGG1 binds free 8-oxoG and this complex functions as an activator of Ras family GTPases...
August 2014: Free Radical Biology & Medicine
Jorge Díaz, Pablo Mendoza, Rina Ortiz, Natalia Díaz, Lisette Leyton, Dwayne Stupack, Andrew F G Quest, Vicente A Torres
Rab5 is a small GTPase that regulates early endosome trafficking and other cellular processes, including cell adhesion and migration. Specifically, Rab5 promotes Rac1 activation and cancer cell migration, but little is known about the upstream regulators of Rab5. We have previously shown that the scaffolding protein Caveolin-1 (CAV1) promotes Rac1 activation and migration of cancer cells. Here, we hypothesized that CAV1 stimulates Rab5 activation, leading to increased Rac1 activity and cell migration. Expression of CAV1 in B16-F10 mouse melanoma and HT-29(US) human colon adenocarcinoma cells increased the GTP loading of Rab5, whereas shRNA-mediated targeting of endogenous CAV1 in MDA-MB-231 breast cancer cells decreased Rab5-GTP levels...
June 1, 2014: Journal of Cell Science
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