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https://www.readbyqxmd.com/read/28911825/paving-the-rho-in-cancer-metastasis-rho-gtpases-and-beyond
#1
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
#2
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
#3
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 the region encompassing the N-terminal to C-terminal Pleckstrin homology domains (PHn-PHc) are auto-inhibited...
September 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28860633/a-cdc42-centered-signaling-unit-is-a-dominant-positive-regulator-of-endothelial-integrity
#4
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
#5
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...
August 30, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28835609/myosin-efflux-promotes-cell-elongation-to-coordinate-chromosome-segregation-with-cell-cleavage
#6
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
https://www.readbyqxmd.com/read/28807941/the-rac-gtpase-in-cancer-from-old-concepts-to-new-paradigms
#7
Marcelo G Kazanietz, María-José Caloca
Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components...
August 14, 2017: Cancer Research
https://www.readbyqxmd.com/read/28799234/arhgef10-knockout-inhibits-platelet-aggregation-and-protects-mice-from-thrombus-formation
#8
D-H Lu, C-C Hsu, S-W Huang, H-J Tu, T-F Huang, H-C Liou, H-M Liao, C-H Chen, W-M Fu, S S-F Gau
Essentials ARHGEF10 single-nucleotide polymorphism provides risk of ischemic and atherothrombotic stroke. The role of ARHGEF10 in platelet function was examined using ARHGEF10 knockout mice. ARHGEF10 deficiency inhibits platelet function and arterial thrombus formation. ARHGEF10 knockout protects mice from stroke-induced infarction. SUMMARY: Background ARHGEF10, a member of the Rho guanine nucleotide exchange factor (GEF) family, stimulates Rho GTPases. Rho GTPases have been reported to regulate a variety of cellular behaviors, such as cell polarity, cytoskeletal organization, and gene transcription...
August 11, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28780965/regulation-of-systemic-autoimmunity-and-cd11c-tbet-b-cells-by-swef-proteins
#9
Michela Manni, Edd Ricker, Alessandra B Pernis
Recent studies have revealed the existence of a T-bet dependent subset of B cells, which expresses unique phenotypic and functional characteristics including high levels of CD11c and CD11b. In the murine system this B cell subset has been termed Age/autoimmune-associated B cells (ABCs) since it expands with age in non-autoimmune mice and it prematurely accumulates in autoimmune-prone strains. The molecular mechanisms that promote the expansion and function of ABCs are largely unknown. This review will focus on the SWEF proteins, a small family of Rho GEFs comprised of SWAP-70 and its homolog DEF6, a newly identified risk variant for human SLE...
July 11, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28775097/platelet-derived-growth-factor-receptor-alpha-pdgfr%C3%AE-and-ras-related-c3-botulinum-toxin-substrate-1-rac1-regulate-mechano-responsiveness-of-lung-fibroblasts
#10
Stephen E McGowan, Diann M McCoy
Platelet-derived growth factor (PDGF)-A, which only signals through PDGF-receptor-alpha (PDGFRα) is required for secondary alveolar septal formation. Although PDGFRα distinguishes mesenchymal progenitor cells during the saccular stage, PDGFRα-expressing alveolar cells persist through adulthood. PDGF-A sustains proliferation, limits apoptosis, and maintains alpha-smooth muscle actin (αSMA) containing alveolar cells, which congregate at the alveolar entry ring at postnatal day (P)12. PDGFRα-expressing, αSMA-containing, alveolar cells re-distribute in the elongating septum, suggesting that they migrate to the alveolar entry rings where mechanical tension is higher...
August 3, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28754687/cells-lay-their-own-tracks-optogenetic-cdc42-activation-stimulates-fibronectin-deposition-supporting-directed-migration
#11
Seth P Zimmerman, Sreeja B Asokan, Brian Kuhlman, James E Bear
Rho GTPase family members are known regulators of directed migration and therefore play key roles in processes including development, immune response and cancer metastasis. However, their individual contributions to these processes are complex. Here, we regulate the activity of two family members, Rac and Cdc42, by optogenetically recruiting specific GEF DH/PH domains to defined regions on the cell membrane. We find that the localized activation of both GTPases produce lamellipodia in cells plated on a fibronectin substrate...
July 28, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28743335/-regulation-of-paxillin-tyrosine-phosphorylation-via-inhibition-of-c-abl-kinase-to-protect-ventilator-induce-lung-injury-in-vivo-in-rats
#12
Rong Zhong, Jun Xiao, Chunguang Dai, Zhihui Yu
OBJECTIVE: To determine whether the inhibition of paxillin tyrosine residues 31 and tyrosine residues 118 (Pxn Y31 and Pxn Y118) phosphorylation via inhibition of c-Abl kinase will effectively block its downstream effector molecules vessel endothelium-cadherin (VE-cad), and whether Rho/Rho kinase activation which will induce the vascular barrier dysfunction. METHODS: Ninety healthy male Sprague-Dawley (SD) rats were randomly divided into nine groups (each n =10)...
July 2017: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue
https://www.readbyqxmd.com/read/28742002/cdc42-activation-state-affects-its-localization-and-protein-levels-in-fission-yeast
#13
Miguel Estravís, Sergio Antonio Rincón, Elvira Portales, Pilar Pérez, Beatriz Santos
Rho GTPases control polarized cell growth and are well-known regulators of exocytic and endocytic processes. Cdc42 is an essential GTPase, conserved from yeast to humans, that is critical for cell polarization. Cdc42 is negatively regulated by the GTPase-activating proteins (GAPs) and the GDP dissociation inhibitors (GDIs), and positively regulated by guanine nucleotide exchange factors (GEFs). Cdc42 GTPase can be found in a GTP- or GDP-bound state, which determines the ability to bind downstream effector proteins and activate signalling pathways...
July 26, 2017: Microbiology
https://www.readbyqxmd.com/read/28712859/tyr42-phosphorylation-of-rhoa-gtpase-promotes-tumorigenesis-through-nuclear-factor-nf-%C3%AE%C2%BAb
#14
Jae-Gyu Kim, Kyoung-Chan Choi, Chang-Won Hong, Hwee-Seon Park, Eun-Kyoung Choi, Yong-Sun Kim, Jae-Bong Park
Dysregulation of reactive oxygen species (ROS) levels is implicated in the pathogenesis of several diseases, including cancer. However, the molecular mechanisms for ROS in tumorigenesis have not been well established. In this study, hydrogen peroxide activated nuclear factor-κB (NF-κB) and RhoA GTPase. In particular, we found that hydrogen peroxide lead to phosphorylation of RhoA at Tyr42 via tyrosine kinase Src. Phospho-Tyr42 (p-Tyr42) residue of RhoA is a binding site for Vav2, a guanine nucleotide exchange factor (GEF), which then activates p-Tyr42 form of RhoA...
July 14, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28701658/drosophila-dock-family-protein-zizimin-involves-in-pigment-cell-differentiation-in-pupal-retinae
#15
Fumito Ozasa, Kazushige Morishita, Ngoc Anh Suong Dang, Seiji Miyata, Hideki Yoshida, Masamitsu Yamaguchi
The dedicator of cytokinesis (DOCK) family proteins are known as one of guanine nucleotide exchange factors (GEFs), that contribute to cellular signaling processes by activating small G proteins. Although mammalian Zizimin is known to be a GEF for Cdc42 of Rho family small GTPase, its role in vivo is not well understood. Here we studied in vivo function of Drosophila Zizimin (Ziz). Knockdown of Ziz in eye imaginal discs induced the rough eye phenotype accompanied with fusion of ommatidia, loss of bristles and loss of pigments...
July 13, 2017: Cell Structure and Function
https://www.readbyqxmd.com/read/28657426/oncogenic-ect2-signaling-regulates-rrna-synthesis-in-nsclc
#16
Verline Justilien, Kayla C Lewis, Nicole R Murray, Alan P Fields
The Rho GTPase family members Rac1, Cdc42 and RhoA play key contributory roles in the transformed phenotype of human cancers. Epithelial Cell Transforming Sequence 2 (Ect2), a guanine nucleotide exchange factor (GEF) for these Rho GTPases, has also been implicated in a variety of human cancers. We have shown that Ect2 is frequently overexpressed in both major forms of non-small cell lung cancer (NSCLC), lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC), which together make up approximately 70% of all lung cancer diagnoses...
June 28, 2017: Small GTPases
https://www.readbyqxmd.com/read/28652571/discovery-of-long-range-inhibitory-signaling-to-ensure-single-axon-formation
#17
Tetsuya Takano, Mengya Wu, Shinichi Nakamuta, Honda Naoki, Naruki Ishizawa, Takashi Namba, Takashi Watanabe, Chundi Xu, Tomonari Hamaguchi, Yoshimitsu Yura, Mutsuki Amano, Klaus M Hahn, Kozo Kaibuchi
A long-standing question in neurodevelopment is how neurons develop a single axon and multiple dendrites from common immature neurites. Long-range inhibitory signaling from the growing axon is hypothesized to prevent outgrowth of other immature neurites and to differentiate them into dendrites, but the existence and nature of this inhibitory signaling remains unknown. Here, we demonstrate that axonal growth triggered by neurotrophin-3 remotely inhibits neurite outgrowth through long-range Ca(2+) waves, which are delivered from the growing axon to the cell body...
June 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28644070/particulate-matter-disrupts-human-lung-endothelial-cell-barrier-integrity-via-rho-dependent-pathways
#18
Ting Wang, Yuka Shimizu, Xiaomin Wu, Gabriel T Kelly, Xiaoyan Xu, Lichun Wang, Zhongqing Qian, Yin Chen, Joe G N Garcia
Increased exposure to ambient particulate matter (PM) is associated with elevated morbidity and mortality in patients with cardiopulmonary diseases and cancer. We and others have shown that PM induces lung microvascular barrier dysfunction which potentially enhances the systemic toxicity of PM. However, the mechanisms by which PM disrupts vascular endothelial integrity remain incompletely explored. We hypothesize that PM induces endothelial cell (EC) cytoskeleton rearrangement via Rho GTPase-dependent pathways to facilitate vascular hyperpermeability...
July 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28585695/the-rhogap-myo9b-promotes-bone-growth-by-mediating-osteoblastic-responsiveness-to-igf-1
#19
Brooke K McMichael, Yong-Hoon Jeong, Justin A Auerbach, Cheol-Min Han, Ryan Sedlar, Vikram Shettigar, Martin Bähler, Sudha Agarwal, Do-Gyoon Kim, Beth S Lee
The Ras homolog A (RhoA) subfamily of Rho guanosine triphosphatases (GTPases) regulates actin-based cellular functions in bone such as differentiation, migration, and mechanotransduction. Polymorphisms or genetic ablation of RHOA and some of its regulatory guanine exchange factors (GEFs) have been linked to poor bone health in humans and mice, but the effects of RhoA-specific GTPase-activating proteins (GAPs) on bone quality have not yet been identified. Therefore, we examined the consequences of RhoGAP Myo9b gene knockout on bone growth, phenotype, and cellular activity...
June 6, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28554775/zonula-occludens-2-regulates-rho-proteins-activity-and-the-development-of-epithelial-cytoarchitecture-and-barrier-function
#20
Arturo Raya-Sandino, Alejandro Castillo-Kauil, Alaide Domínguez-Calderón, Lourdes Alarcón, David Flores-Benitez, Francisco Cuellar-Perez, Bruno López-Bayghen, Bibiana Chávez-Munguía, José Vázquez-Prado, Lorenza González-Mariscal
Silencing Zonula occludens 2 (ZO-2), a tight junctions (TJ) scaffold protein, in epithelial cells (MDCK ZO-2 KD) triggers: 1) Decreased cell to substratum attachment, accompanied by reduced expression of claudin-7 and integrin β1, and increased vinculin recruitment to focal adhesions and stress fibers formation; 2) Lowered cell-cell aggregation and appearance of wider intercellular spaces; 3) Increased RhoA/ROCK activity, mediated by GEF-HI recruitment to cell borders by cingulin; 4) Increased Cdc42 activity, mitotic spindle disorientation and the appearance of cysts with multiple lumens; 5) Increased Rac and cofilin activity, multiple lamellipodia formation and random cell migration but increased wound closure; 6) Diminished cingulin phosphorylation and disappearance of planar network of microtubules at the TJ region; and 7) Increased transepithelial electrical resistance at steady state, coupled to an increased expression of ZO-1 and claudin-4 and a decreased expression of claudin-2 and paracingulin...
May 26, 2017: Biochimica et Biophysica Acta
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