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https://www.readbyqxmd.com/read/29313423/rho-guanosine-nucleotide-exchange-factors-are-not-such-bad-guys-after-all-in-cancera
#1
Javier Robles-Valero, L Francisco Lorenzo-Martín, Isabel Fernández-Pisonero, Xosé R Bustelo
Rho GDP/GTP exchange factors (GEFs), the enzymes that trigger the stimulation of Rho GTPases during cell signaling, are widely deemed as potential therapeutic targets owing to their protumorigenic functions. However, the sparse use of animal models has precluded a full understanding of their pathophysiological roles at the organismal level. In a recent article in Cancer Cell, we have reported that the Vav1 GEF unexpectedly acts as a tumor suppressor by mediating the noncatalytic nucleation of cytoplasmic complexes between the E3 ubiquitin ligase Cbl-b and the active Notch1 intracellular domain (ICN1)...
January 9, 2018: Small GTPases
https://www.readbyqxmd.com/read/29233866/rho-gtpase-signaling-complexes-in-cell-migration-and-invasion
#2
REVIEW
Campbell D Lawson, Anne J Ridley
Cell migration is dependent on the dynamic formation and disassembly of actin filament-based structures, including lamellipodia, filopodia, invadopodia, and membrane blebs, as well as on cell-cell and cell-extracellular matrix adhesions. These processes all involve Rho family small guanosine triphosphatases (GTPases), which are regulated by the opposing actions of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPase activity needs to be precisely tuned at distinct cellular locations to enable cells to move in response to different environments and stimuli...
December 12, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29199510/regulation-of-rhoa-gtpase-and-novel-target-proteins-for-rock
#3
Eun-Kyoung Choi, Jae-Gyu Kim, Hee-Jun Kim, Jung-Yoon Cho, Hwalrim Jeong, Yohan Park, Rokibul Islam, Cuong Kim Cap, Jae-Bong Park
Rho GTPases play significant roles in cellular function and their activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), providing activation and inactivation of these GTPases, respectively. Active GTP-bound form of RhoA activates its effector proteins while the inactive GDP-bound form of RhoA exists in a RhoA-RhoGDI (guanine nucleotide dissociation inhibitor) complex in the cytosol. In particular, IκB kinase γ IKKγ/NF-κB essential modulator (NEMO) plays a role as a GDI displacement factor (GDF) for RhoA activation through binding to RhoA-RhoGDI complex...
December 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/29189096/regulation-and-functions-of-rhou-and-rhov
#4
Richard G Hodge, Anne J Ridley
Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases that have some atypical properties compared with classical Rho family members, such as the presence of N- and C-terminal extension regions, unusual GDP/GTP cycling and post-translational modification by palmitoylation but not prenylation. Their activity and localization is regulated by the N-terminal and C-terminal regions, and so far no GEFs or GAPs have been identified for them...
November 30, 2017: Small GTPases
https://www.readbyqxmd.com/read/29188751/go-with-the-flow-gef-h1-mediated-shear-stress-mechanotransduction-in-neutrophils
#5
Noah Fine, Ioannis D Dimitriou, Robert Rottapel
Neutrophils in circulation experience significant shear forces due to blood flow when they tether to the vascular endothelium. Biochemical and biophysical responses of neutrophils to the physical force of flowing blood modulate their behavior and promote tissue recruitment under pro-inflammatory conditions. Neutrophil mechanotransduction responses occur through mechanisms that are not yet fully understood. In our recent work, we showed that GEF-H1, a RhoA specific guanine nucleotide exchange factor (GEF), is required to maintain neutrophil motility and migration in response to shear stress...
November 30, 2017: Small GTPases
https://www.readbyqxmd.com/read/29173011/genetic-deletion-of-the-rho-gef-net1-impairs-mouse-macrophage-motility-and-actin-cytoskeletal-organization
#6
Yan Zuo, John d'Aigle, Anjali Chauhan, Jeffrey A Frost
Macrophages are innate immune cells that constantly patrol an organism to fulfill protective and homeostatic roles. Previous studies have shown that Rho GTPase activity is required for macrophage mobility, yet the roles of upstream regulatory proteins controlling Rho GTPase function in these cells are not well defined. Previously we have shown that the RhoA GEF Net1 is required for human breast cancer cell motility and extracellular matrix invasion. To assess the role of Net1 in macrophage motility, we isolated bone marrow macrophage (BMM) precursors from wild type and Net1 knockout mice...
November 26, 2017: Small GTPases
https://www.readbyqxmd.com/read/29168172/extracellular-adenosine-induced-rac1-activation-in-pulmonary-endothelium-molecular-mechanisms-and-barrier-protective-role
#7
Anita Kovacs-Kasa, Kyung Mi Kim, Mary Cherian-Shaw, Stephen M Black, David J Fulton, Alexander D Verin
We have previously shown that Gs-coupled adenosine receptors (A2a) are primarily involved in adenosine-induced human pulmonary artery endothelial cell (HPAEC) barrier enhancement. However, the downstream events that mediate the strengthening of the endothelial cell (EC) barrier via adenosine signaling are largely unknown. In the current study we tested the overall hypothesis that adenosine-induced Rac1 activation and EC barrier enhancement is mediated by Gs-dependent stimulation of cAMP-dependent Epac1-mediated signaling cascades...
November 23, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29136506/a-paradoxical-tumor-suppressor-role-for-the-rac1-exchange-factor-vav1-in-t-cell-acute-lymphoblastic-leukemia
#8
Javier Robles-Valero, L Francisco Lorenzo-Martín, Mauricio Menacho-Márquez, Isabel Fernández-Pisonero, Antonio Abad, Mireia Camós, María L Toribio, Lluis Espinosa, Anna Bigas, Xosé R Bustelo
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation...
November 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29130632/dock3-related-neurodevelopmental-syndrome-biallelic-intragenic-deletion-of-dock3-in-a-boy-with-developmental-delay-and-hypotonia
#9
Aiko Iwata-Otsubo, Alyssa L Ritter, Brooke Weckselbatt, Nicole R Ryan, David Burgess, Laura K Conlin, Kosuke Izumi
Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6-12 of the DOCK3 gene at 3p21...
November 12, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29121646/the-phosphomimetic-mutation-of-syndecan-4-binds-and-inhibits-tiam1-modulating-rac1-activity-in-pdz-interaction-dependent-manner
#10
Aniko Keller-Pinter, Bettina Ughy, Monika Domoki, Aladar Pettko-Szandtner, Tamas Letoha, Jozsef Tovari, Jozsef Timar, Laszlo Szilak
The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs). Here we report a novel regulatory mechanism of Rac1 activity, which is controlled by a phosphomimetic (Ser179Glu) mutant of syndecan-4 (SDC4). SDC4 is a ubiquitously expressed transmembrane, heparan sulfate proteoglycan...
2017: PloS One
https://www.readbyqxmd.com/read/29061365/rho-specific-guanine-nucleotide-exchange-factors-rho-gefs-inhibition-affects-macrophage-phenotype-and-disrupts-golgi-complex
#11
Wei Chen, Yue Zhao, Xian C Li, Jacek Z Kubiak, Rafik M Ghobrial, Malgorzata Kloc
Macrophages play crucial role in tissue homeostasis and the innate and adaptive immune response. Depending on the state of activation macrophages acquire distinct phenotypes that depend on actin, which is regulated by small GTPase RhoA. The naive M0 macrophages are slightly elongated, pro-inflammatory M1 are round and M2 anti-inflammatory macrophages are elongated. We showed previously that interference with RhoA pathway (RhoA deletion or RhoA/ROCK kinase inhibition) disrupted actin, produced extremely elongated (hummingbird) macrophage phenotype and inhibited macrophage movement toward transplanted hearts...
October 20, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29055010/an-excitable-rho-gtpase-signaling-network-generates-dynamic-subcellular-contraction-patterns
#12
Melanie Graessl, Johannes Koch, Abram Calderon, Dominic Kamps, Soumya Banerjee, Tomáš Mazel, Nina Schulze, Jana Kathrin Jungkurth, Rutuja Patwardhan, Djamschid Solouk, Nico Hampe, Bernd Hoffmann, Leif Dehmelt, Perihan Nalbant
Rho GTPase-based signaling networks control cellular dynamics by coordinating protrusions and retractions in space and time. Here, we reveal a signaling network that generates pulses and propagating waves of cell contractions. These dynamic patterns emerge via self-organization from an activator-inhibitor network, in which the small GTPase Rho amplifies its activity by recruiting its activator, the guanine nucleotide exchange factor GEF-H1. Rho also inhibits itself by local recruitment of actomyosin and the associated RhoGAP Myo9b...
October 20, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29046349/differential-regulation-of-the-rac1-gtpase-activating-protein-gap-bcr-during-oxygen-glucose-deprivation-in-hippocampal-and-cortical-neurons
#13
Katharine R Smith, Dipen Rajgor, Jonathan G Hanley
Brain ischemia causes oxygen and glucose deprivation (OGD) in neurons, triggering a cascade of events leading to synaptic accumulation of glutamate. Excessive activation of glutamate receptors causes excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts, but the mechanisms that underlie this difference are unclear. Signalling via Rho-family small GTPases, their upstream Guanine nucleotide Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs) is differentially dysregulated in response to OGD/ischemia in hippocampal and cortical neurons...
October 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28970150/flcn-the-causative-gene-for-birt-hogg-dub%C3%A3-syndrome
#14
REVIEW
Laura S Schmidt, W Marston Linehan
Germline mutations in the novel tumor suppressor gene FLCN are responsible for the autosomal dominant inherited disorder Birt-Hogg-Dubé (BHD) syndrome that predisposes to fibrofolliculomas, lung cysts and spontaneous pneumothorax, and an increased risk for developing kidney tumors. Although the encoded protein, folliculin (FLCN), has no sequence homology to known functional domains, x-ray crystallographic studies have shown that the C-terminus of FLCN has structural similarity to DENN (differentially expressed in normal cells and neoplasia) domain proteins that act as guanine nucleotide exchange factors (GEFs) for small Rab GTPases...
January 15, 2018: Gene
https://www.readbyqxmd.com/read/28911825/paving-the-rho-in-cancer-metastasis-rho-gtpases-and-beyond
#15
REVIEW
Sepp Jansen, Reinoud Gosens, Thomas Wieland, Martina Schmidt
Malignant carcinomas are often characterized by metastasis, the movement of carcinoma cells from a primary site to colonize distant organs. For metastasis to occur, carcinoma cells first must adopt a pro-migratory phenotype and move through the surrounding stroma towards a blood or lymphatic vessel. Currently, there are very limited possibilities to target these processes therapeutically. The family of Rho GTPases is an ubiquitously expressed division of GTP-binding proteins involved in the regulation of cytoskeletal dynamics and intracellular signaling...
September 11, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28910410/the-function-of-drosophila-larval-class-iv-dendritic-arborization-sensory-neurons-in-the-larval-pupal-transition-is-separable-from-their-function-in-mechanical-nociception-responses
#16
Hannah E Brown, Trishna Desai, Allison J Murphy, Harshida Pancholi, Zachary W Schmidt, Hannah Swahn, Eric C Liebl
The sensory and physiological inputs which govern the larval-pupal transition in Drosophila, and the neuronal circuity that integrates them, are complex. Previous work from our laboratory identified a dosage-sensitive genetic interaction between the genes encoding the Rho-GEF Trio and the zinc-finger transcription factor Sequoia that interfered with the larval-pupal transition. Specifically, we reported heterozygous mutations in sequoia (seq) dominantly exacerbated the trio mutant phenotype, and this seq-enhanced trio mutant genotype blocked the transition of third instar larvae from foragers to wanderers, a requisite behavioral transition prior to pupation...
2017: PloS One
https://www.readbyqxmd.com/read/28882897/the-tiam1-guanine-nucleotide-exchange-factor-is-auto-inhibited-by-its-pleckstrin-homology-coiled-coil-extension-domain
#17
Zhen Xu, Lokesh Gakhar, Fletcher E Bain, Maria Spies, Ernesto J Fuentes
T-cell lymphoma invasion and metastasis 1 (Tiam1) is a Dbl-family guanine nucleotide exchange factor (GEF) that specifically activates the Rho-family GTPase Rac1 in response to upstream signals, thereby regulating cellular processes including cell adhesion and migration. Tiam1 contains multiple domains, including an N-terminal pleckstrin homology coiled-coiled extension (PHn-CC-Ex) and catalytic Dbl homology and C-terminal pleckstrin homology (DH-PHc) domain. Previous studies indicate that larger fragments of Tiam1, such as the region encompassing the N-terminal to C-terminal pleckstrin homology domains (PHn-PHc), are auto-inhibited...
October 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28860633/a-cdc42-centered-signaling-unit-is-a-dominant-positive-regulator-of-endothelial-integrity
#18
J Amado-Azevedo, N R Reinhard, J van Bezu, R X de Menezes, V W van Beusechem, G P van Nieuw Amerongen, V W M van Hinsbergh, P L Hordijk
Endothelial barrier function is carefully controlled to protect tissues from edema and damage inflicted by extravasated leukocytes. RhoGTPases, in conjunction with myriad regulatory proteins, exert both positive and negative effects on the endothelial barrier integrity. Precise knowledge about the relevant mechanisms is currently fragmented and we therefore performed a comprehensive analysis of endothelial barrier regulation by RhoGTPases and their regulators. Combining RNAi with electrical impedance measurements we quantified the relevance of 270 Rho-associated genes for endothelial barrier function...
August 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28859988/cytoskeletal-remodeling-via-rho-gtpases-during-oxidative-and-thermal-stress-in-caenorhabditis-elegans
#19
Rahul Patel, Sindhu Sriramoji, Marena Marucci, Ibrahim Aziz, Sejal Shah, Federico Sesti
Biological systems are highly sensitive to changes in their environment. Indeed, the molecular basis of the environmental stress response suggests that the specialized stress responses share more commonalities than previously believed. Here, we used the nematode C. elegans to gain insight into the role of Rho signaling during two common environmental challenges, oxidative and thermal stress. In response to heat shock (HS), wild type (N2) worms demonstrated reduced viability which was rescued by genetic suppression of CDC42 and RHO-1...
October 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28835609/myosin-efflux-promotes-cell-elongation-to-coordinate-chromosome-segregation-with-cell-cleavage
#20
Emilie Montembault, Marie-Charlotte Claverie, Lou Bouit, Cedric Landmann, James Jenkins, Anna Tsankova, Clemens Cabernard, Anne Royou
Chromatid segregation must be coordinated with cytokinesis to preserve genomic stability. Here we report that cells clear trailing chromatids from the cleavage site by undergoing two phases of cell elongation. The first phase relies on the assembly of a wide contractile ring. The second phase requires the activity of a pool of myosin that flows from the ring and enriches the nascent daughter cell cortices. This myosin efflux is a novel feature of cytokinesis and its duration is coupled to nuclear envelope reassembly and the nuclear sequestration of the Rho-GEF Pebble...
August 23, 2017: Nature Communications
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