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Rozprawy doktorskie na temat „Rho GTPases Signaling”

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Data publikacji: 7 września 2023

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1

Fransson, Åsa. "Cell signaling by Rho and Miro GTPases : Studies of Rho GTPases in Cytoskeletal Reorganizations and of Miro GTPases in Mitochondrial Dynamics". Doctoral thesis, Uppsala University, Ludwig Institute for Cancer Research, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8514.

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The Ras superfamily of GTPases embraces six major branches of proteins: the Ras, Rab, Ran, Arf, Rho and Miro subfamilies. The majority of GTPases function as binary switches that cycle between active GTP-bound and inactive GDP-bound states. This thesis will focus primarily on the biological functions of the Rho and Miro proteins. The Rho GTPases control the organization of the actin cytoskeleton and other associated activities, whereas the Miro GTPases are regulators of mitochondrial movement and morphology.

A diverse array of cellular phenomena, including cell movement and intracellular membrane trafficking events, are dependent on cytoskeletal rearrangements mediated by Rho GTPases. Although human Rho GTPases are encoded by 20 distinct genes, most studies involving Rho GTPases have focused on the three representatives RhoA, Rac1 and Cdc42, which each regulate specific actin-dependent cellular processes. In an effort to compare the effects of all Rho GTPase members in the same cell system, we transfected constitutively active Rho GTPases in porcine aortic endothelial (PAE) cells and examined their effects on the organization of the actin cytoskeleton. We identified a number of previously undetected roles of the different members of the Rho GTPases. Moreover, we demonstrated that the downstream effectors of Rho GTPases have a broader specificity than previously thought.

In a screen for novel Ras-like GTPases, we identified the Miro GTPases (Mitochondrial Rho). In our characterization of Miro, we established that these proteins influence mitochondrial morphology and serve functions in the transport of mitochondria along the microtubule system. Additionally, we provided evidence that Miro can be under control of calcium signaling pathways. Mitochondria are highly dynamic organelles that undergo continuous change in shape and distribution. Defects in mitochondrial dynamics are associated with several neurodegenerative diseases. In conclusion, our findings have contributed to a deeper understanding of the biological roles of Rho and Miro GTPases.

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2

Fransson, Åsa. "Cell signaling by Rho and Miro GTPases : studies of Rho GTPases in cytoskeletal reorganizations and of Miro GTPases in mitochondrial dynamics /". Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8514.

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3

Chan, Man-lok Mandy, i 陳文樂. "A study of RhoV and PAK4 signaling in hepatocarcinogenesis". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47053434.

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Sipes, Nisha Schuler. "Cdc42 signaling in extracellular matrix remodeling in three dimensions". University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1253622562.

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5

Picard, Mariêve. "The role of the small Rho GTPases in the signaling mechanisms mediated by the netrin-1 receptor UNC5a". Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=19255.

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Netrin-1 is a bifunctional chemotropic cue that attracts or repels different classes of axons through the Deleted in Colorectal Cancer (DCC) and the UNC5 receptors (UNC5a, b, c and d). DCC is implicated in mediating both responses whereas UNC5 receptors are strictly involved in the repulsive events. The intracellular molecular mechanisms underlying axon growth and guidance are still unclear but it is known that this process requires remodeling of the actin cytoskeleton. There is now compelling evidence that Rho GTPases, in particular RhoA, Rac1 and Cdc42, are important signaling elements within the neuronal growth cone and we hypothesize that they link netrin-1-mediated UNC5a signaling to cytoskeletal remodeling and repulsion. In the first part of this thesis, we have demonstrated that overexpression of UNC5a or a mutant lacking the cytoplasmic tail of the receptor in N1E-115 neuroblastoma cells expressing netrin-1, stimulated the formation of neurites in a netrin-1-dependent manner. Rho GTPase activation assays in COS-7 cells expressing UNC5a also showed a transient 1.5-, 2- and 9-fold increase in the levels of activated Rac1, Cdc42 and RhoA, respectively, after two minutes of netrin-1 stimulation. Fluorescence Resonance Energy Transfer (FRET) in N1E-115 cells revealed that UNC5a strongly activated RhoA at neurite tips and activated Rac1 in the absence of its cytoplasmic domain, suggesting the presence of a signaling partner. These results demonstrate that Rho GTPases are important signaling components of the netrin-1 receptor UNC5a. In the second part, we have investigated the implication of Rac1, Cdc42 and RhoA in the netrin-1-mediated inhibitory effect of embryonic mouse dorsal root ganglia (DRG) axons. We found that netrin
Les nétrines sont des facteurs chémotropiques qui attirent ou repoussent différentes classes d'axones en agissant via les récepteurs DCC et UNC5 (UNC5a, b, c et d). DCC est impliqué dans l'attraction et dans la répulsion du cône de croissance tandis que les récepteurs UNC5 sont impliqués seulement dans la répulsion. Les mécanismes intracellulaires régissant le guidage axonal sont encore très peu connus. Cependant, il est clair que le mouvement dynamique du cône de croissance via le remodelage de son cytoskelette d'actine est requis durant les événements de guidage. Les activités des GTPases Rho, en particulier RhoA, Rac1 et Cdc42, font parties des mécanismes moléculaires qui régissent la migration axonale et nous croyons que ces protéines jouent un rôle primordial durant les événements de répulsion induits par le récepteur UNC5a. Dans la première partie de ce mémoire, nous avons démontré que UNC5a ainsi qu'un mutant tronqué de son domaine cytoplasmique induisent la formation de neurites dans les cellules murines de neuroblastomes, suivant la liaison de la nétrine-1. De plus, UNC5a augmente de 1.5, 2 et 9 fois le niveau d'activation de Rac1, Cdc42 et RhoA, respectivement, après deux minutes de stimulation avec la nétrine-1 dans les fibroblastes. Nous démontrons également par « Fluorescence Resonance Energy Transfer » (FRET) que UNC5a active fortement RhoA à l'extrémité de la neurite et active également Rac1, lorsque tronqué de son domaine cytoplasmique, suggérant la possibilité que le récepteur agisse via un partenaire. Ces résultats indiquent que les GTPases Rho sont des éléments majeurs de la signalisation de la nétrine-1 et de son récepteur UNC5a. Dans la seconde partie, nous

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6

Hoop, Alyssa N. "Rho-Family GTPase Signaling in the Nervous System: An Analysis of the C. elegans RhoGEF UNC-73". University of Toledo / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1404733888.

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7

Saint-Cyr, Proulx Étienne. "Role of the Rho GTPases in the signaling mechanisms regulated by the axon guidance cue Netrin-1 receptors deleted in colorectar cancer and Unc5H1". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98788.

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Chemotropic cues guide the migrating axons of neurons in the developing nervous system. Netrins are bifunctional guidance cues, attracting or repelling different classes of axons. The attraction to netrins is mediated by DCC whereas repulsion is achieved through Unc5H receptors. In this thesis, we demonstrate that Rho GTPases are required for embryonic spinal commissural axon outgrowth induced by Netrin-1. Using N1E-115 neuroblastoma cells, we have found that Rac1 and Cdc42 activities are required for DCC-induced neurite outgrowth. In fibroblasts, DCC was found to trigger actin reorganization through activation of Rac1. Moreover, we show that Unc5H1 triggers actin reorganization through activation of RhoA in fibroblasts. Using N1E-115 cells we found that Unc5H1 induces neurite outgrowth in a Rac1- and Cdc42-dependent manner. The studies presented in this thesis demonstrate that Rho GTPases are major signaling components of Netrin-1 receptors DCC and Unc5H1.

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Silva, Gisele Espinha Teixeira da. "Sinalização da GTPase RhoA nas respostas celulares após estresse genotóxico promovido por radiação ultravioleta". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-19102016-165552/.

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A via de sinalização da GTPase RhoA atua em diversos processos celulares. Para avaliar o comportamento de RhoA, após estresse causado por radiação ultravioleta, foram gerados clones mutantes que expressam RhoA em seu estado constitutivamente ativo e dominante negativo. Após exposição das linhagens à radiação ultravioleta, observou-se uma maior sensibilidade e um maior tempo de recuperação das linhagens quando a atividade de RhoA é reduzida. Estes prejuízos no reparo prejudicaram a proliferação e sobrevivência celular quando da deficiência na atividade de RhoA. Em linhagens deficientes na via de NER, percebemos que estas linhagens possuem uma capacidade ainda mais reduzida de reparo quando a atividade de RhoA é inibida.
The RhoA GTPase signaling pathway acts on many cellular processes. To evaluate this possible RhoA function after stress caused by ultraviolet radiation, mutant clones expressing RhoA in its constitutively active or dominant negative forms were generated. After exposure of the cells to ultraviolet radiation, cell lines showed a higher sensitivity and a delayed recovery capacity when the RhoA activity is reduced. The impaired repair reduced the cells proliferation and survival under RhoA deficiency. In cell lines deficient in NER pathway, we notice that these cell lines, have a further reduced ability to repair damaged DNA under RhoA inhibition.

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9

Osaki, Juliana Harumi. "O papel de RhoA e Rac1 GTPases nas respostas celulares após danos no DNA induzidos por radiação ionizante gama". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-22092015-075415/.

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O mecanismo pelo qual uma célula responde a algum dano no seu material genético é extremamente importante. Isto ocorre pela rápida ativação da maquinaria de reparo de danos no DNA, a qual é composta por uma rede intrincada de sinalização proteica, culminando no reparo do DNA; porém se o dano for irreparável ocorre ativação de mecanismos de morte celular. RhoA,e Rac1 pertencem a família das pequenas proteínas sinalizadoras Rho GTPases, as quais atuam como interruptores moleculares ciclando entre estado ativo (ligada a GTP) e inativo (ligada a GDP). Os componentes desta família estão relacionados ao controle dos mais diversos processos celulares como, por exemplo, remodelamento do citoesqueleto, migração, adesão, endocitose, progressão do ciclo celular e oncogênese. No entanto, apesar das proteínas Rho GTPases estarem envolvidas em um amplo espectro de atividades biológicas, há poucas informações sobre seu papel na manutenção da integridade genômica quando células são submetidas a algum agente genotóxico. Para investigar o envolvimento das GTPases RhoA e Rac1 nas respostas de células submetidas a radiação gama, foram gerados, a partir de células de carcinoma de cervix humano - HeLa, sublinhagens clonais mutantes de RhoA e Rac1 expressando exogenamente RhoA constitutivamente ativa (HeLa-RhoA V14), RhoA dominante negativa (HeLa-RhoA N19), Rac1 constitutivamente ativa (HeLa-Rac1 V12) e Rac1 dominante negativa (HeLa-Rac N17). Após estas linhagens celulares serem expostas a diferentes doses de radiação gama, observamos que ambas GTPases, RhoA e Rac1, são ativadas em resposta aos efeitos da radiação. Além disso, a modulação da atividade destas enzimas, através das mutações, levou a uma alteração das respostas celulares frente aos danos no DNA, como uma redução da capacidade de reparar quebras simples e duplas nas fitas do DNA. Por outro lado, a deficiência de RhoA ou Rac1 GTPase levou a uma redução da ativação de Chk1 e Chk2 ou da fosforilação da histona H2AX, respectivamente, prejudicando os mecanismos de detecção de danos no DNA e levando as células a permanecerem mais tempo nos pontos de checagem G1/S e/ou G2/M do ciclo celular. Esses fatores contribuíram de modo expressivo para a redução da proliferação e sobrevivência celular levando as células à morte. Por fim, ensaios celulares de reparo de danos de um DNA exógeno através de mecanismos de Recombinação Homóloga (HR) e Recombinação Não-Homóloga de extremidades (NHEJ), demonstraram que a inibição da atividade de RhoA reduz significativamente a eficiência de ambas vias de reparo. Desta maneira, este trabalho demonstra e reforça a existência de mais um viés de atuação das pequenas GTPases RhoA e Rac1, agora em células HeLa, nas respostas celulares aos danos induzidos por exposição a radiação gama, modulando a sobrevivência, proliferação e indiretamente modulando resposta ao reparo do DNA através da via de Recombinação Homóloga e Não-Homóloga
The mechanism by which a cell responds to DNA damage is extremely important. This occurs by a quick activation of the DNA damage repair machinery, which consists of an intricate protein signaling network culminating in DNA repair. But if the damages are irreparable occurs there is activation of cell death mechanisms. RhoA and Rac1 belong to family of small Rho GTPases, signaling proteins that act as molecular switches cycling between the active state (GTP-bound) and inactive state (GDP-bound). Members of this family are implicated in the control of diverse cellular process such as cytoskeletal remodeling, migration, adhesion, endocytosis, cell cycle progression, and oncogenesis. However, despite Rho proteins are involved in a broad spectrum of biological activities, there is just a few information about their roles in the maintenance of genomic integrity, that is, when the cells are subjected to some kinf of genotoxic agent. To investigate the involvement of the GTPases RhoA and Rac1 in cellular responses to gamma radiation, we generated from human cervix carcinoma cells - HeLa, clonal sublines of RhoA and Rac1 mutants, exogenous and stably expressing the constitutively active RhoA (HeLa-RhoA V14), the dominant negative RhoA (HeLa-RhoA N19), the constitutively active Rac1 (HeLa-Rac1 V12) and the dominant negative Rac1 (HeLa-Rac1 N17). After all these cell lines have been exposed to different doses of gamma radiation, we found that both GTPases, RhoA and Rac1, are activated in response to the radiation effects. Furthermore, the modulation of two enzymes activity, by using the mutant clones, led to a change in cellular responses to the DNA damage, as the reduction in the capacity of repairing DNA single and double strand breaksr. On the other hand, the deficiency of RhoA or Rac1 GTPase led to a reduction of Chk1 and Chk2 activation, or on the phosphorylation of histone H2AX, respectively, hindering the mechanisms of DNA damage detection and arresting cells in the G1/S and/or G2/M checkpoints of cell cycle. These factors significantly contributed to the reduction of cell proliferation and survival, leading cells to death. Finally, cellular assays of DNA damage repair of exogenous DNA by Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ), demonstrated that RhoA inhibition significantly reduced the repair efficiency of both pathways. Thus, this work demonstrates and reinforces the existence of other biological functions of small GTPases RhoA and Rac1 in HeLa cells, by regulating cellular responses to DNA damage induced by exposure to gamma radiation, modulating the survival, proliferation and indirectly modulating the response to DNA damage repair pathway through the Homologous Recombination and Non-Homologous Recombination

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Marshall, Andrew Keith. "Signalling through Rho GTPases in cardiomyocytes". Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/6962.

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Endothelin-1 (ET-1) promotes changes in gene/protein expression in cardiomyocytes leading to hypertrophy. This results from activation of intracellular signalling pathways including small G proteins that activate protein kinases. Thus, ET-1 activates RhoA that stimulates ROCK and PKN, and Ras that promotes activation of extracellular signal-regulated kinases 1/2 (ERK1/2). Microarrays were used to dissect the roles of ERK1/2 vs RhoA in the cardiomyocyte transcriptomic response to ET-1 using PD184352 and C3 endotoxin from C. botulinum (C3T) for selective inhibition of the ERK1/2 cascade and RhoA, respectively. Microarray data were analysed using GeneSpring and data were validated by qPCR. ERK1/2 signalling positively regulated ~65% of the early gene expression response to ET-1 with a small (~2%) negative effect, whereas RhoA signalling positively regulated ~11% of the early gene expression response to ET-1 with a greater (~14%) negative contribution. Of RNAs non-responsive to ET-1, 66 or 448 were regulated by PD184352 or C3T, respectively, indicating that RhoA had a more significant effect on baseline RNA expression. mRNAs upregulated by ET-1 encoded several receptor ligands (e.g. Ereg, Areg) and transcription factors (e.g. Abra/STARS, Srf) that potentially propagate the response. Published studies suggest that PKN1 (activated by RhoA) is important in cardiomyocyte gene expression. Adenoviruses were generated to overexpress FLAG-tagged PKN1 in cardiomyocytes for protein kinase studies. Unexpectedly, PKN1 was not activated by ET-1, but was activated by oxidative stress, insulin, or hyperosmotic shock, stimuli that do not activate RhoA. Thus, PKN1 is not necessarily an effector of RhoA in cardiomyocytes. In conclusion, ERK1/2 dominates over RhoA in the early transcriptomic response to ET-1. RhoA plays a major role in maintaining baseline RNA expression but, as with upregulation of Abra/Srf by ET-1, RhoA may regulate changes in RNA expression over longer times. However, the effects of RhoA on cardiomyocyte gene expression are unlikely to be mediated through PKN1.

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Leszczyńska, Katarzyna. "Signalling and function of the small Rho GTPase RhoJ in endothelial cells". Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/1495/.

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RhoJ is an endothelial expressed Rho GTPase, and its knock-down impairs endothelial cell (EC) migration and tubulogenesis, increases stress fibre (SF) and focal adhesion (FA) numbers. This work aimed to determine the intracellular localisation of RhoJ, identify its binding partners, test how it is activated and further explore its function in ECs. Endogenous RhoJ localised to FAs and overexpression of its active mutant (daRhoJ) promoted EC migration, and diminished FA and SF numbers. In addition to FAs, overexpressed RhoJ localised also to endosomes and RhoJ knock-down slightly delayed transferrin recycling. Vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2) and thrombin activated RhoJ in ECs. PAK-interacting exchange factor β (βPIX) and G protein-coupled receptor kinase-interacting target 1 (GIT1), which promote FA disassembly, were identified as RhoJ-binding partners. RhoJ co-localised with these proteins in ECs, and βPIX knock-down and to a lesser extent GIT1 knock-down reduced RhoJ localisation to FAs. Overexpression of daRhoJ increased the amount of GIT1 and βPIX in FAs, and increased the total amount of the βPIX protein in ECs. In conclusion, RhoJ localises to FAs, promotes EC migration, regulates FA and SF numbers, interacts with βPIX and GIT1 and is activated by pro-angiogenic factors.

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Hu, Shuang. "Rho GTPase Signaling Modulates Neurotransmission in Caenorhabditis elegans". University of Toledo / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1365182177.

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Cordeiro, Joao. "Modulation of Rho GTPase signalling during vaccinia virus infection". Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/17273/.

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Infection by vaccinia virus leads to reorganization of the actin cytoskeleton, changes in cell adhesion, loss of contact inhibition and stimulation of cell motility. Previous work by the group has led to the identification of a viral gene, F11L, which is highly conserved among the orthopoxvirus genomes and is essential for this virus-induced cell mobility. F11L has been shown to interact with the RhoA but does not interact with the two other 'classical’ members of the family Rac1 and Cdc42. Understanding the molecular interaction of F11L and RhoA as well as investigating additional Rho binding partners was the basis of my thesis project with a view to obtain additional insights into the role of Rho GTPase manipulation during the vaccinia life cycle. Deletion of F11L from the virus genome results in reduced virus release and smaller plaque sizes. Characterization of the interaction between F11L and RhoA revealed that it occurs via a region of limited sequence homology to the RhoA effector ROCKI, in the C-terminal part of the molecule. Interestingly, generation of a recombinant mutant virus (F11L-VK) that is unable to bind RhoA leads to an intermediate phenotype between ΔF11L and WR in terms of viral plaque size. Further bioinformatic analysis revealed a region in the N-terminus of F11L with limited sequence homology to hDia2C, a RhoD effector. Biochemical analysis led to the identification of this site as the RhoD binding domain in F11L. Importantly, this study revealed that F11L interacts directly with different Rho GTPases via unique motifs to induce cell motility and facilitate enhanced virus cell-to-cell spread. Furthermore, work done in collaboration with the laboratory of Mariano Esteban in Madrid using a mouse model of infection shows that in contrast to wild-type vaccinia, infection with ΔF11L does not result in animal death. Additionally, the F11L-VK virus shows limited spread in vivo but still induces animal death albeit at a later stage when compared to wild-type vaccinia. These results suggest that F11L has additional functions besides interacting with RhoA, consistent with my observations that it can interact with other Rho GTPases. These studies can provide valuable information about the importance of Rho GTPase manipulation for the life cycle of vaccinia virus but also indicate the potential for the genetic manipulation of F11L in existing poxvirus vectors that may improve their therapeutic potential, safety, immunogenicity and/or oncolytic activity.

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Wallace, S. "Analysis of Rho GTPase signalling pathways regulating epithelial morphogenesis". Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19565/.

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Rho GTPases are molecular switches controlling many aspects of cell behaviour, including cell cycle progression, cell division, migration and morphology. The activity of Rho proteins is regulated by conformational changes induced by binding of guanine nucleotides, with GTP-bound Rho being active and GDP-bound Rho inactive. Families of regulatory proteins have evolved to catalyse cycling between these states. Guanine nucleotide exchange factors (GEFs) catalyse nucleotide exchange, allowing GDP to dissociate and GTP to bind to Rho, thus activating it. GTPase activating proteins (GAPs) enhance the intrinsic GTPase activity of Rho, leading to GTP hydrolysis and inactivation of Rho. Active GTP-bound Rho can interact with and regulate a number of effector proteins, through which cellular responses are elicited. Epithelial cells are a specialized cell type that form selectively permeable barriers between different compartments of a multicellular organism, and thus play an important role in tissue organization and homeostasis. The formation of cell-cell junctions, including tight junctions and adherens junctions, is critical for this function. Experiments carried out in model organisms and in cell culture have shown that Rho GTPases are important regulators of epithelial morphogenesis. I sought to identify components of the signalling pathways through which Rho GTPases regulate junction formation. RNAi screens were carried out with siRNA libraries targeting Rho GEFs, GAPs and effectors, using tight junction formation in the human bronchial epithelial cell line 16HBE as readout. This approach led to the identification of three Rho effector proteins required for junction formation, namely PRK2, PAK4 and PAR6B.

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Grant, Gary. "Rho GTPase signalling in cilia and blood vessel lumen formation". Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/17044/.

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Vascular endothelial cells, the cells that line blood vessels, play roles both in the development of the circulatory system through providing blood vessel integrity, and its homeostasis through responding to changes in the local environment. During development, the acquisition of functionality of new blood vessels, some of which form from pre-existing ones through the process of angiogenesis, requires generation of endothelial lumens to carry the blood, during a process known as lumenogenesis. Throughout new blood vessel formation, endothelial cells go through coordinated and complex cell shape changes and polarity changes driven by Rho GTPase activity. Rho GTPases control intracellular actin dynamics and therefore affect all stages of new vessel growth. Precise control of Rho GTPase signalling is through a range of upstream activator and downstream effector proteins. Here we have investigated the role of two proteins involved in the antagonistic Rho/ Rac pathways during angiogenesis and lumen formation. Results presented in this thesis describe a role for the Rac guanine nucleotide exchange factor (GEF) DOCK4, and Cdc42 GEF DOCK9, in controlling lumen formation in an organotypic in vitro angiogenesis assay, through both common and distinct cellular mechanisms. The RhoA effector ROCK1/2 controls RhoA- mediated cytoskeletal remodelling and have been shown to control angiogenesis in tissue culture assays. Here we use in vivo knockout mouse model to show that ROCK2 controls actin- based filopodia formation and vessel integrity, as well as other cytoskeletal processes such as ciliogenesis. Further investigation showed that loss of ROCK2 results in aberrant lumen formation. We also highlight a new role for ROCK2 signalling in primary cilia growth and abundance in endothelial cells which may also impact on lumen formation. In summary, this work has identified novel molecular pathways that control lumen formation in endothelial cells. These results build on the current understanding of molecular mechanisms involved in lumen formation, and may also lead to better understanding of the function of ROCK, a potential therapeutic target in therapeutic angiogenesis strategies.

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Mitchell, Dianne Courtenay. "Regulation and function of the Rho GTPase mediated signaling pathways in metastasis and lenticular differentiation". Diss., Texas A&M University, 2003. http://hdl.handle.net/1969.1/5845.

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Modulation of the actin-based cytoskeleton and transcription factor regulation are merely two essential functions in a wide array of cellular activities that the Rho family of small GTPases is responsible for mediating. Aberrations in, or loss of, Rho GTPase signaling has been found to lead to multiple pathologies, including both metastatic progression and lenticular differentiation leading to cataractogenesis. This study has examined the transcriptional regulation of the metastasis suppressor, KiSS-1. Although the mechanism by which KiSS-1 modulates an anti-metastatic effect is not entirely known, it is known that KiSS-1 mediates stress fiber formation, increased adhesion and reduced migratory and invasive properties through modulation of the Rho family of small GTPases. The loss of KiSS-1 that commonly occurs during metastatic progression, leads to a loss of proper Rho GTPase regulation. This study has examined how KiSS-1 is regulated in two tissue types, breast and skin, and how the loss of AP-2(alpha) and DRIP-130, respectively, leads to the progression of breast cancer and melanoma. In addition, this study has also looked at the importance of Rac1 expression and function in the lens epithelium. Activation of Rac1 and its downstream effector, SRF, have been shown to be key regulators in lens cell differentiation, possibly leading to lens opacification via its transcriptional control of the structural crystallins within the lens. The results of this dissertation research have made significant strides in understanding the nature of the anti-metastatic effects registered by the novel KiSS-1 peptide and its cognate GPCR. Additionally, it has shed light on the Rho family regulation of lens epithelial cell differentiation, indicating the elaborate involvement of Rac1 in mediating lens fiber development. In all, this research has determined previously unknown roles of small molecule GTPases in both the progression of metastasis, as well as in normal and abnormal lens cell differentiation.

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Quist, Sven Roy. "Role of Rac1 signalling in epidermal tumour formation". Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708007.

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Mota, Monica Alexandra Domingues Serrador da. "Control of programmed cell death by RHO like GTPases activated signalling cascades in the developing neuron". Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271401.

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Nikolaidou, Kyriaki. "Investigation of the role RHO GTPase signalling in cell shape changes during Drosophila Morphogenesis". Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396361.

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Fediuk, Jena. "Thromboxane receptor signaling and Rho GTPase activation on actin polymerization and contraction in hypoxic neonatal pulmonary arterial myocytes". Am J Physiol Lung Cell Mol Physiol, 2012. http://hdl.handle.net/1993/23862.

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INTRODUCTION: Persistent Pulmonary Hypertension of the Newborn (PPHN) is defined as the failure of normal circulatory relaxation in the lungs at birth. Hypoxia is known to impede postnatal disassembly of the actin cytoskeleton in pulmonary arterial (PA) myocytes. Actin polymerization (APM), regulated by Rho GTPases, stabilizes force generation. We studied basal and thromboxane (TP)-induced APM and contraction in normoxic and hypoxic PA myocytes and rings. We also examined the downstream signaling pathways regulating hypoxia and TP-induced APM, and the role that actin plays in TP receptor internalization. METHODS: Smooth muscle myocytes from 2nd to 6th generation PAs of newborn piglets were cultured and exposed to hypoxia (10% O2) or normoxia (21% O2) for 72 hrs, then challenged with 10-6M TP-agonist U46619. APM was quantified by laser-scanning cytometry and stress fiber isolation. Downstream signaling pathways of TP receptor were studied by immunoprecipitation, Rhotekin-RBD and PAK-PBD affinity precipitation, Western blot, immunofluoresence and ELISA. Isometric force to serial concentrations of U46619 was measured in resistant PAs from PPHN and 3-day control swine. RESULTS: Hypoxia induced 2-fold APM via alpha- and gamma-actin isoforms, which contributed to increase U46619-induced contraction. Hypoxia decreased TP association with G12/13 in favor of Gαq. Basal RhoA and Cdc42 activity increased in hypoxia, while Rac activity decreased. U46619-challenge did not further alter RhoA activity in hypoxic cells, but increased Cdc42 and Rac activity. Hypoxia increased phosphorylation of LIMK and PAK, unaltered by U46619. Association of Cdc42 with N-WASp decreased in hypoxia, but increased after U46619 exposure. Jasplakinolide significantly stabilized gamma filaments, increasing force generation; cytochalasin D depolymerized all actin isoforms, which attenuated contractile force. Both actin-modifying agents prevented TP endocytosis in NM, while normalizing TP internalization in HM. CONCLUSIONS: PA myocytes exhibit marked RhoA- and Rac-dependent APM in hypoxia. The additional APM response to U46619 challenge is independent of RhoA, but requires Cdc42 signaling. Hypoxia induces APM in PA myocytes, particularly causing an increase in filamentous alpha- and gamma-actin that contributes to increased U46619-induced force generation, a characteristic of PPHN. Dynamic actin also facilitates internalization of the TP receptor. Determining the mechanism that controls TP-mediated APM maybe beneficial as a potential target for PPHN.

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Alayed, Khaled. "MULTIOMICS EVALUATION OF THE EFFECT OF EZRIN INHIBITOR IN DIFFUSE LARGE B CELL LYMPHOMA REVEALS DYSREGULATION OF BCR SIGNALING, RHO GTPASE SIGNALING AND APOPTOSIS". Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1552485811716089.

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Fortin, Ensign Shannon Patricia. "The TWEAK-Fn14 Ligand Receptor Axis Promotes Glioblastoma Cell Invasion and Survival Via Activation of Multiple GEF-Rho GTPase Signaling Systems". Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/293463.

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Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK-Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-kB dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.

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Arens, Stefan [Verfasser], i Theresia [Akademischer Betreuer] Stradal. "Characterization of type III secreted bacterial virulence factors that interfere with Rho GTPase signalling / Stefan Arens ; Betreuer: Theresia Stradal". Münster : Universitäts- und Landesbibliothek Münster, 2014. http://d-nb.info/1138279897/34.

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Fortin, Ensign Shannon Patricia. "THE TWEAK-FN14 LIGAND RECEPTOR AXIS PROMOTES GLIOBLASTOMA CELL INVASION AND SURVIVAL VIA ACTIVATION OF MULTIPLE GEF-RHO GTPASE SIGNALING SYSTEMS". Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/528171.

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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK- Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-B dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.

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Smallman, Matthew John. "Spatial regulation of Rho GTPase signalling during root hair development in Arabidopsis thaliana is reliant upon the guanine nucleotide dissociation inhibitor SCN1". Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496221.

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The scn1-1 mutants of Arabidopsis are characterised by spatially deregulated sites of root hair growth. This studydemonstrates that this phenotype is the result of the loss of regulation of members of the plant specific sub-family of Rho small GTPases by the Guanine nucleotide Dissociation Inhibitor (GDI), encoded by SCN1. The small GTPases R0P2, R0P4 and R0P5 of Arabidopsis are members of the I subset of type I ROPs that terminate with a conserved CXXL box and undergo 3 prenylation. These small GTPases are expressed in trichoblasts, and localize in patters suggestive of specific roles throughout root hair development. Loss-of function ROP2, R0P4 or ROP5 mutants display distinct root hair phenotypes lending support to the hypothesis that : R0P2, R0P4 and ROP5 control the establishment of the site of root hair initiation and subsequent tip-growth. Our findings also reveal SCNl/GDIl and R0P2 co-localize in a similiar pattern in developing root hairs in planta, but SCNl/GDIl is able to associate directly with ROP2, ROP4 and ROP5 in vitro.This suggests root hair morphogenesis relies on the negative regulation of ROP activity by SCNl/GDI 1 and is further supported by morphological phenotypes of scnl-l plants which can be rescued by the over expression of CFP:GD11 fusion placed under the control of the root hair specific PRP3 (Proline Rich Protein3) promoter. These observations imply that ROPs can be selectively sequestered away from the from plasma membrane of elongating root hairs during tip growth thereby promoting growth along a planar axis. Differences in the observed binding affinity of R0P2 in comparison to R0P4 and ROPS for SCNl/GDIl provides evidence that the CXXL box may play a critical role in ROP regulation, and that R0P2 and R0P4 are differentially prenylated.

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Kitade, Yuki. "Functional analysis of signaling components regulating pathogenicity and asexual/sexual development in Bipolaris maydis". Kyoto University, 2019. http://hdl.handle.net/2433/242717.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(農学)
甲第21840号
農博第2353号
新制||農||1069(附属図書館)
学位論文||H31||N5212(農学部図書室)
京都大学大学院農学研究科地域環境科学専攻
(主査)教授田中千尋, 教授本田与一, 准教授刑部正博
学位規則第4条第1項該当

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Dubash, Adi Dara Burridge Keith. "Regulation of RhoA GTPase signaling by guanine nucleotide exchange factors in response to extracellular matrix adhesion and DNA damage". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2407.

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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2009.
Title from electronic title page (viewed Sep. 3, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell and Developmental Biology within the School of Medicine." Discipline: Cell and Developmental Biology; Department/School: Medicine.

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28

Schenck, Annette. "CYFIP, a protein family implicated in neuronal connectivity, links Rac1 GTPase signalling to the fragile X mental retardation protein". Université Louis Pasteur (Strasbourg) (1971-2008), 2003. http://www.theses.fr/2003STR13175.

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Le syndrome de l'X Fragile, qui constitue la forme la plus fréquente de retard mental héréditaire, est du à l'absence de FMRP, une protéine de liaison à l'ARN qui régulerait la traduction au niveau synaptique. Afin de mieux comprendre le role de FMRP, nous avons réalisé un criblage double-hybride dans la levure pour identifier certains de ses interacteurs. Deux protéines ont été isolées, CYFIP1 et CYFIP2 (Cytoplasmic FMRP Interacting Proteins 1/2). Ces deux protéines cytoplasmiques sont hautement homologues mais interagissent différement avec les deux autres protéines de la famille FXR, FXR1P et FXR2P. Le site de liaison à CYFIP recouvre le site d'homo- et d'hétérodimérisation de FMRP, suggérant que la liaison à CYFIP pourrait moduler l'activité de FMRP. D'autre part, l'interaction entre CYFIP1 et Rac1 a été démontrée précédemment. Rac1, une protéine de la famille des Rho GTPase, est un des principaux régulateurs de la réorganisation du cytosquelette d'actine et joue un role clé dans la maturation et la maintenance des épines dendritiques, structures synaptiques riches en actine anormalement développées chez les patients X-Fragile et dans les souris invalidées pour FMRP. De nombreux gènes des voies Rho/Rac étant impliqués dans des retards mentaux, Rac1, CYFIP1 et FMRP pourraient participer à une voie commune contrôlant la morphogénèse synaptique et le fonctionnement cognitif. Pour valider cette hypothèse in vivo, nous avons choisi Drosophila melanogaster comme organisme modèle. Nous avons découvert que CYFIP y est très exprimé dans le système nerveux embryonnaire, et s'accumule notamment dans les axones centraux et aux jonctions neuro-musculaires (JNM). Des mutations de CYFIP causent des défauts de croissance, de ramification et de connexion des axones et conduisent à une morphologie anormale des synapses des JNM. Ainsi, l'absence de CYFIP provoque des défauts similaires à ceux précedemment décrits chez les mutants dFMR1 et/ou dRac1. L'analyse des interactions génétiques et biochimiques entre ces trois protéines suggère que, lorsque la voie est activée, dRac1 inhibe CYFIP qui régule à son tour négativement dFMR1
Fragile X Syndrome is the most frequent form of hereditary mental retardation and caused by the absence of FMRP, an RNA binding protein that seems to regulate local protein translation at synapses. To better understand the physiological function of FMRP, we conducted a yeast two-hybrid screen to determine interacting proteins. We identified CYFIP1 and CYFIP2 (Cytoplasmic FMRP Interacting Proteins 1/2), two highly homologous cytoplasmic proteins, which show a different pattern of interaction with the two FMRP-related proteins FXR1P and FXR2P. The CYFIP binding site of FMRP overlaps with its homo- and heteromerisation domain, suggesting that binding to CYFIP may modulate FMRP function. Importantly, CYFIP1 has been previously reported to interact with Rac1. Rac1, a Rho GTPase, is a key regulator of actin cytoskeleton remodelling with a well-established role in maturation and maintenance of dendritic spines, which are actin-rich synaptic structures that are abnormally developed in Fragile X patients and FMRP null mice. Since several genes of Rac/Rho signalling pathways are implicated in mental retardation, our work suggested that Rac1, CYFIP and FMRP work in a common pathway determining synapse morphogenesis and cognitive function. To address this hypothesis in vivo, we have chosen the fruitfly Drosophila melanogaster as a genetic model organism. Drosophila CYFIP, a previously undescribed gene, is highly expressed in the embryonic nervous system, where it strongly accumulates in central axons and at the neuromuscular junction (NMJ). CYFIP mutations induce defects in axon growth, branching and pathfinding and result in abnormal synapse morphology at the neuromuscular junction. Hence, loss of CYFIP involves defects that have been previously described in dFMR1 and/or dRac1 mutants. Analyses of biochemical and genetic interactions amongst these three proteins suggest that upon activation, dRac1 acts antagonistically on CYFIP, which in turn negatively regulates dFMR1

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Carie, Adam E. "Tumor suppressive effects of the Beta-2 adrenergic receptor and the small GTPase RhoB". [Tampa, Fla.] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002330.

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Lam, Jonathan Lam. "Identification of mammalian cell signaling in response to plasma membrane perforation: Endocytosis of Listeria monocytogenes and The Repair Machinery". The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1543497502225763.

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Mills, Evan. "Engineering Synthetic Control over Rho GTPases using Ca2+ and Calmodulin Signaling". Thesis, 2012. http://hdl.handle.net/1807/34811.

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Engineered protein systems have been created to impart new functions, or “re-program” mammalian cells for applications including cancer and HIV/AIDS therapies. The successful development of mammalian cells for re-programming will depend on having well-defined, modular systems. Migration is a particularly important cell function that will determine the efficiency and efficacy of many re-programming applications in vivo, and Rho proteins are responsible for regulation of cell migration natively. While there have been several reports of photo-activated Rho proteins, no strategy has been developed such that Rho proteins and cell migration can be controlled by a variety of extracellular stimuli that may be compatible with signaling in large organisms. Here, several methods are described for engineering Ca2+-sensitive Rho proteins so that the large, natural toolbox of Ca2+-mobilizing proteins can use the Ca2+ intermediate to activate Rho proteins in response to a variety of exogenous stimuli, including chemicals, growth factors, and light. First, an unreported calmodulin binding site was identified in RhoA. This knowledge was used to create a tandem fusion of RhoA and calmodulin that mediated Ca2+-sensitive bleb retraction in response to a variety of Ca2+-elevating chemicals. Ca2+-mobilizing modules including channelrhodopsin-2 and nicotinic acetylcholine receptor α4 were used for light- and acetylcholine-dependent bleb retraction. Second, a more robust morphology switch was created by embedding a calmodulin binding site into RhoA to enable Ca2+-responsive bleb formation. A wider range of Ca2+-mobilizing modules were also used here including LOVS1K/Orai1 and vascular endothelial growth factor 2. Combining Ca2+-mobilizing and Ca2+-responsive modules increased amoeboid-like cell migration in wound closure and transwell assays. Finally, the embedded peptide design was applied to Rac1 and Cdc42 to enable control of new morphologies and migration modes. The modular Ca2+ control over Rho proteins developed here is an important contribution to cell re-programming because it shows that control over cell migration can be rewired in a way that is flexible and tunable.

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Di, Ciano-Oliveira Caterina. "Signaling pathways linking osmotic stress to adaptive responses: Roles for Rho family GTPases". 2006. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=449940&T=F.

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Zhou, Hua. "Modulation of squamous carcinoma cell motility by RhoA and Cdc42-PAK1 signaling /". 2004. http://wwwlib.umi.com/dissertations/fullcit/3149705.

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Dietz, Christian [Verfasser]. "Analyses of small Rho-GTPases signaling molecules during vertebrate development and angiogenesis / vorgelegt von Christian Tobias Dietz". 2011. http://d-nb.info/1011266997/34.

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Du, Jing. "Unbiased Expression Profiling Identifies a Novel Notch Signaling Target RND1 as Regulator of Angiogenesis". Thesis, 2019. https://doi.org/10.7916/d8-pmrg-g821.

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Notch signaling controls normal and pathological angiogenesis through transcriptional regulation of a wide network of target genes. Despite intensive studies of the endothelial Notch function, a comprehensive list of Notch-regulated genes, especially direct transcriptional targets, has not been assembled in endothelial cells (ECs). Here we uncovered novel EC Notch targets that are rapidly regulated by Notch signaling using several unbiased in vivo and in vitro screening approaches that captured genes regulated within 6 hours or less of Notch signal activation. We used a gamma-secretase inhibitor in neonates to profile Notch targets in the brain endothelium using the RiboTag technique, allowing for isolation of endothelial specific mRNA from a complex tissue without disrupting cell-cell contact. We used two types of primary cultured endothelial cells to define ligand-specific Notch targets by tethered-ligand stimulation. The identified Notch targets were validated by determining their regulation within one to two hours of EGTA-mediated Notch activation. By comparing significantly regulated genes in each of the screens, we assembled a comprehensive database of potential Notch targets in endothelial cells. Of particular interest, we uncovered G protein pathway related genes as potential novel Notch targets. We focused on a novel candidate target passing selection criteria after all screens, a small GTPase RND1. RND1(Rho GTPase1) regulates cytoskeleton arrangement through Rho and Ras signaling. RND1 was validated as an endothelial Notch target in multiple endothelial cell types. In Human Umbilical Vein Endothelial Cells (HUVECs) we established angiogenic activity for RND1 that included regulation of cell migration towards VEGF and function in sprouting angiogenesis. We established that Notch and RND1 suppressed Ras activation but had no effects on Rho activation in HUVECs. These results demonstrate that RND1 expression is regulated by Notch signaling in endothelium and suggest that RND1 functions downstream of Notch in sprouting angiogenesis, revealing an unexplored role of endothelial Notch in regulating G protein pathways.

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Beane, Wendy Scott. "Building Gene Regulatory Networks in Development: Deploying Small GTPases". Diss., 2007. http://hdl.handle.net/10161/96.

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Kuo, Jia-Yu, i 郭佳瑜. "Mechanistic study of lovastatin modulating Rho GTPase signaling in astrocytes". Thesis, 2008. http://ndltd.ncl.edu.tw/handle/3y59hb.

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碩士
國立陽明大學
神經科學研究所
97
Statin is the inhibitor of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. It is commonly used to treat patients suffering from hypercholesterolemia. Recent studies have demonstrated that statin also has some effects on nervous system. Previous studies from this laboratory already found that the combined treatment of lovastatin and β-cyclodextrin induced the process outgrowth and actin cytoskeleton reorganization, namely decreased actin rings and actin filaments in hippocampal astrocytes. Nonetheless, it showed no similar effect on hippocampal neurons. It is known that Rho protein regulates the organization of actin cytoskeleton and the formation of actin filaments within cells. However, the mechanism by which lovastatin decreases actin filaments in hippocampal astrocytes is still unknown. In my study, I found that lovastatin increased the expression of RhoA but inhibited the translocation of RhoA to the plasma membrane. In contrast, lovastatin didn’t influence the expression of RhoA in hippocampal neurons.

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Justa-Schuch, Daniela. "Regulation of septum formation by RHO4 GTPase signalling in Neurospora crassa". Doctoral thesis, 2010. http://hdl.handle.net/11858/00-1735-0000-0006-ADB3-9.

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Vogt, Nico. "Governing fungal polar cell extension: Analysis of Rho GTPase and NDR kinase signalling in Neurospora crassa". Doctoral thesis, 2008. http://hdl.handle.net/11858/00-1735-0000-000D-F161-9.

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Sterk, Carolin Christin. "The role of Rho5 in oxidative stress response and glucose signalling in Saccharomyces cerevisiae". Doctoral thesis, 2021. https://repositorium.ub.uni-osnabrueck.de/handle/urn:nbn:de:gbv:700-202106034890.

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Rho-GTPases are essential signalling proteins which regulate a multitude of central cellular processes that are vital for organisms to thrive and adapt to changing environments. Many regulatory networks involving Rho proteins have first been elucidated in the model yeast Saccharomyces cerevisiae, in which Rho5 emerges as a central hub connecting different signalling pathways, such as the responses to cell wall stress, high medium osmolarity, and oxidative stress. In this work, the rapid translocation of Rho5 to mitochondria as reaction to oxidants and glucose starvation was thoroughly investigated. The studies on structure-function relationships was focussed on the C-terminal region of the Rho5 which in other Rho-type GTPases determines their spatio-temporal distribution and contributes to their physiological function. The C-terminal end of these GTPases is considered to be a hypervariable region (HPR) that consists of a polybasic region (PBR) and its preceding amino acid residues, followed by the CAAX motif which becomes prenylated at its cysteine residue. These motifs are conserved in the yeast Rho5 where the PBR contains a serine residue as a putative phosphorylation target. Moreover, Rho5 of S. cerevisiae is characterized by an extension preceding the PBR that comprises 98 amino acid residues. While substitutions of the serine residue within the PBR for either phosphomimetic or non-phosphorylatable residues indicate that it is of minor physiological importance, deletion analyses of the yeast-specific extension showed that it is required for proper localization of Rho5 to the plasma membrane. As expected, substitution of the cysteine residue within the CAAX motif also prevented proper plasma membrane localization, accompanied by a loss of function both with respect to oxidative stress response and glucose starvation. Results from studies employing a trapping-device of GFP-Rho5 to the mitochondrial surface indicate that the GTPase needs to be activated at the plasma membrane by its dimeric GDP/GTP exchange factor (GEF) which is composed of Dck1 and Lmo1, in response to stress conditions. The trimeric DLR complex is then capable of rapidly translocate to mitochondria and fulfil its functions at the organelle. This view was supported by the finding that a constitutively active Rho5 variant restored function when trapped to mitochondria. Interestingly, Rho5 requires the dimeric GEF for the translocation process under oxidative stress while Dck1 and Lmo1 can reach the mitochondria independent from each other. Finally, the human Rho5 homolog Rac1 cannot complement the defects of a rho5 deletion and does not show a proper intracellular distribution, unless its C-terminal end is equipped with the yeast-specific extension. Taken together, the results of this thesis contributed to a better understanding of the structure-function relationships of Rho5 and its human homolog Rac1.

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Vogt, Nico [Verfasser]. "Governing fungal polar cell extension : analysis of Rho GTPase and NDR kinase signalling in Neurospora crassa / vorgelegt von Nico Vogt". 2008. http://d-nb.info/993187846/34.

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Justa-Schuch, Daniela [Verfasser]. "Regulation of septum formation by RHO4 GTPase signalling in Neurospora crassa / vorgelegt von Daniela Justa-Schuch". 2010. http://d-nb.info/1005299900/34.

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Schilling, Kerstin [Verfasser]. "The role of PIX Rho GTPase exchange factors in signal pathways of the immune system : analysis of signaling capacities of αPIX-/- and αPIX-/- βPIX+/- lymphocytes ; generation of a βPIX conditional knockout / vorgelegt von Kerstin Schilling". 2008. http://d-nb.info/1000868648/34.

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