Дисертації з теми "ACKR4"
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Garcia, Ibanez Laura. "Decision events in the germinal centre : the role of ACKR4." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7365/.
Повний текст джерелаFumagalli, Amos. "Deciphering CXCR4 and ACKR3 interactomes reveals an influence of ACKR3 upon Gap junctional intercellular communication." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT036.
Повний текст джерелаThe Atypical Chemokine Receptor 3 (ACKR3) and CXCR4 are two G protein-coupled receptors (GPCR) belonging to the CXC chemokine receptor family. Both receptors are activated upon CXCL12 binding and are over-expressed in various tumours, including glioma, where they have been found to promote proliferation and invasive behaviours. Upon CXCL12 binding, CXCR4 activates canonical GPCR signalling pathways involving Gαi protein and β-arrestins. In addition, CXCR4 was found to interact with several proteins able to modify its signalling, trafficking and localization. In contrast, the cellular pathways underlying ACKR3-dependent effects remain poorly characterized. Several reports show that ACKR3 engages β-arrestin-dependent signalling pathways, but its coupling to G proteins is restricted to either specific cellular populations, including astrocytes, or occurs indirectly via its interaction with CXCR4. ACKR3 also associates with the epidermal growth factor receptor to promote proliferation of tumour cells in an agonist-independent manner. These examples suggest that the extensive characterization of ACKR3 and CXCR4 interactomes might be a key step in understanding or clarifying their roles in physiological and pathological contexts. This thesis addressed this issue employing an affinity purification coupled to high-resolution mass spectrometry proteomic strategy that identified 19 and 151 potential protein partners of CXCR4 and ACKR3 transiently expressed in HEK-293T cells, respectively. Amongst ACKR3 interacting proteins identified, we paid particular attention on the gap junction protein Connexin-43 (Cx43), in line with its overlapping roles with the receptor in the control of leukocyte entry into the brain, interneuron migration and glioma progression. Western blotting and BRET confirmed the specific association of Cx43 with ACKR3 compared to CXCR4. Likewise, Cx43 is co-localized with ACKR3 but not CXCR4 in glioma initiating cell lines, and ACKR3 and Cx43 are co-expressed in astrocytes of the sub-ventricular zone and surrounding blood vessels in adult mouse brain, suggesting that both proteins form a complex in authentic cell or tissue contexts. Further functional studies showed that ACKR3 influences Cx43 trafficking and functionality at multiple levels. Transient expression of ACKR3 in HEK-293T cells to mimic ACKR3 overexpression detected in several cancer types, induces Gap Junctional Intercellular Communication (GJIC) inhibition in an agonist-independent manner. In addition, agonist stimulation of endogenously expressed ACKR3 in primary cultured astrocytes inhibits Cx43-mediated GJIC through a mechanism that requires activation of Gαi protein, and dynamin- and β-arrestin2-dependent Cx43 internalisation. Therefore, this thesis work provides the first functional link between the CXCL11/CXCL12/ACKR3 axis and gap junctions that might underlie their critical role in glioma progression
Heuninck, Joyce. "Analysis of CXCR4 and ACKR3 oligomerisation." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT018.
Повний текст джерелаDuring my PhD, I focused on two chemokine receptors, CXCR4 and ACKR3. They have several important physiological functions, such as chemotaxis of immune cells. However, on the other hand, when their function is disturbed, they are involved in different immunological pathologies and cancer. Both receptors recognise the same chemokine, CXCL12 and many studies have reported a crosstalk between CXCR4 and ACKR3. However, the mechanisms behind this crosstalk are still poorly understood. This crosstalk can occur because both receptors are competing for CXCL12, at the level of signalling pathways or due to the formation of complexes between CXCR4 and ACKR3 receptors, called oligomers. The oligomers might have specific pharmacological properties different from the receptor monomers. Oligomeric complexes have been described since the nineties. Most of the studies on these oligomers were performed on heterologous expression systems, but still a lot of debate exists about their existence and their role in native tissues. One of the reasons behind this controversy is that studying oligomers in a native context is complicated, especially because we often lack the molecular tools for these studies.The first objective of my PhD was to generate efficient tools to study the existence of CXCR4 and ACKR3 oligomers in native systems. In collaboration with laboratories from Amsterdam and Ghent, we have developed fluorescent nanobodies, small antibodies produced by llamas. These specific tools allow the detection of receptors endogenously expressed at the cell surface. In order to fluorescently label these nanobodies, we have used an original strategy that can specifically attach the fluorophore to the C-terminus of the nanobody. Interestingly, the fluorescent nanobodies retain high affinity and specificity for their target. With these nanobodies, I have demonstrated the existence of CXCR4 oligomers in cell lines that endogenously express CXCR4. We are currently investigating the existence of ACKR3 oligomers.The second objective of my PhD consists of defining the functional roles of these oligomers. I have shown that CXCR4/ACKR3 hetero-oligomers have specific binding characteristics. It seems that CXCL12 is binding only to ACKR3 within this hetero-oligomer and that ACKR3 impairs the CXCL12 binding to CXCR4 within the hetero-oligomer. This is interesting, since we also have demonstrated that CXCL12 is binding much faster on CXCR4 than on ACKR3.In addition, I have studied the consequences of this negative cooperativity within the CXCR4/ACKR3 hetero-oligomer on different signalling pathways. We have compared conditions where the receptor was expressed alone or when receptors were co-expressed. No major modifications have been found on their signalling properties. However, when investigating the internalisation of CXCR4 and ACKR3, it seems that CXCR4/ACKR3 hetero-oligomers remain blocked on the cellular surface.This opens interesting perspectives, since it is the first time CXCR4 oligomers have been detected at an endogenous level. Moreover, the observation of a different internalisation pattern of the hetero-oligomer is a first step to further investigate the specific roles of these oligomers in the crosstalk between the receptors
Pallas, Kenneth James. "The role of ACKR2 in inflammatory pathologies." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6807/.
Повний текст джерелаGallego, Carmen. "Interactions hôte-virus : la chimiokine CXCL12 et ses récepteurs CXCR4 et ACKR3 dans le cycle de vie du papillomavirus humain et la carcinogènese associée." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS337.
Повний текст джерелаHuman papillomavirus (HPV) are part of our virome and infect cutaneous and mucosal sites. Most infections are asymptomatic or only cause benign lesions that are controlled by the host defence mechanisms, which take place both at the epithelial and the immune system levels. However, persistent infections with certain mucosal HPV types at high-risk for cancer development, cause virtually all cases of cervical cancers, a majority of anogenital cancers and an increasing proportion of oropharyngeal cancers. Prophylactic vaccines are efficient in preventing mucosal HPV types-associated lesions but currently, there is no antiviral treatment for an established HPV infection. In this doctoral thesis, we aimed at investigating host factors involved in HPV life cycle and carcinogenesis at two levels: the infected keratinocyte and the immune system. Studies in the context of certain immunodeficient patients (WHIM syndrome, WS) with selective susceptibility to HPV pathogenesis have identified the CXCL12 chemokine and its classical G protein-coupled receptor CXCR4 (whose mutations are causing the WS) as host susceptibility factors that act as gatekeepers of HPV life cycle. CXCL12/CXCR4 together with ACKR3, the second receptor of CXCL12 with an atypical decoy activity, can modulate both epithelial and immune cell anti-viral responses. Therefore, we first investigated the intrinsic contribution of ACKR3 to HPV life cycle in 3D human epithelial cell cultures (3D-EpC), the sole model allowing for HPV replication. Our results indicate that enhanced ACKR3 activity displays pro-oncogenic potential as it shifts HPV productive life cycle toward oncogenesis and that blocking ACKR3 could be an attractive therapeutic approach to favour HPV replication. In addition, we have studied the functional consequences of the productive HPV life cycle in cell-cell communication, being pioneers in setting up FLIP technique in 3D-EpC. Lastly, we investigated the impact of CXCR4 WS-mutation at the cutaneous immune cell level in the context of HPV-induced carcinogenesis. We have thus gained insights into the role of CXCR4 in dendritic cell and Langerhans cell distribution, phenotype and migration and how their deregulation in the context of the WS could account for the selective susceptibility of WS patients to HPV pathogenesis. In conclusion, this work provides new insights into HPV-host interactions at the epithelial and immune cell levels. We have unravelled the central role of ACKR3 in keratinocyte intrinsic response against HPV and deepen our knowledge on the role of CXCL12/CXCR4 in skin immunity in health and in HPV carcinogenesis
Jannat-e-Zereen. "Characterization of the role of ACR4, a receptor like kinase, in Arabidopsis thaliana." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/13252.
Повний текст джерелаCutolo, Pasquale. "Etude de l'interaction structurelle et fonctionnelle entre la chimiokine CXCL12 et ses récepteurs : CXCR4 et ACKR3/CXCR7." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS550/document.
Повний текст джерелаThe axis formed by the chemokine CXCL12 and its receptor CXCR4 is conserved in vertebrates where it plays an important role in embryogenesis and adult life, regulates many processes of immune responses through its functions in cell migration, survival and proliferation.In addition, this axis is involved in pathological processes such as cancers (growth and metastasis) and immune deficiencies and malfunctions (eg deregulated expression, mutations or polymorphisms) and is also hijacked by certain pathogens (eg HIV, human papilloma virus).A large working group is dedicated to this pair as a therapeutic target, but only a compound (ie Plerixafor) achieved approval for clinical use by the potential of this area as a drug target unexplored.Although this axis is the subject of great interest, questions remain about the structural determinants involved in CXCL12 / CXCR4 interaction.However, the recently resolved diffraction structure of CXCR4 gave some clue about these questions, and beyond possible stoichiometry between CXCL12 and CXCR4.Several lines of evidence support the concept that forms CXCR4 homo- and hetero-oligomers (which can contribute to the diversity of the receptor functions), as shown in the diffraction structure, the gain function of a mutant CXCR4 receptor responsible for the syndrome WHIM and allosteric modulation of CXCR4 functions by CXCR7 (ACKR3), the second receptor of the chemokine CXCL12. The ability to form oligomers opens many issues of CXCL12 and its interaction with CXCR4 and CXCR7 / ACKR3.The stoichiometry of this interaction still remains an open question, as the receptor is capable to form oligomers with the same receptor or other receptors, particularly CXCR7 / ACKR3. This receptor, known as scavenger, has not solved structure and the mechanism of interaction with CXCL12 is unknown.To study the interactions CXCL12 / CXCR4 / CXCR7, we applied several molecular modeling techniques such as peptide-peptide docking and molecular dynamics simulations.Objectives of this project were: the resolution of the different stoichiometric forms for the interaction of CXCR4 and CXCL12 (molecular modeling, docking and dynamic); modeling the CXCR7 / ACKR3 receptor structure and its interaction with CXCL12 (homology modeling), with the characterization of domains and residues key in the activation of downstream signaling pathways of the receptor (CXCR7 / ACKR3 mutants); the study and characterization of new innovative tools for the detection of oligomerization of these receptors in endogenous conditions. (Nanobodies, HTRF)The results of the first objective were published in January 2016: PMID 26813575.Modeling of CXCR7 / ACKR3 allowed us to generate several mutants of the receptor to test our hypothesis about the activation pathways.Nanobodies were fully characterized for CXCR4 to be used in a second study to identify oligomeric forms of the receptor in tissues and cells
Woodcock, Thomas M., Tony Frugier, Tan Thanh Nguyen, Bridgette Deanne Semple, Nicole Bye, Matteo Massara, Benedetta Savino, et al. "The scavenging chemokine receptor ACKR2 has a significant impact on acute mortality rate and early lesion development after traumatic brain injury." PUBLIC LIBRARY SCIENCE, 2017. http://hdl.handle.net/10150/626472.
Повний текст джерелаPerpiñá, Viciano Cristina [Verfasser], Carsten [Gutachter] Hoffmann, Martin J. [Gutachter] Lohse, and Elke [Gutachter] Butt-Dörje. "Study of the activation mechanisms of the CXC chemokine receptor 4 (CXCR4) and the atypical chemokine receptor 3 (ACKR3) / Cristina Perpiñá Viciano ; Gutachter: Carsten Hoffmann, Martin J. Lohse, Elke Butt-Dörje." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1222910365/34.
Повний текст джерелаWhyte, Carly Ellyse. "Chemokine-mediated control of immunity to tumours and infectious pathogens." Thesis, 2018. http://hdl.handle.net/2440/128467.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2018
Gravel, Stéphanie. "Étude des mécanismes d'action du récepteur de chimiokine CXCR7/ACKR3." Thèse, 2018. http://hdl.handle.net/1866/21614.
Повний текст джерелаPerpiñá, Viciano Cristina. "Study of the activation mechanisms of the CXC chemokine receptor 4 (CXCR4) and the atypical chemokine receptor 3 (ACKR3)." Doctoral thesis, 2020. https://doi.org/10.25972/OPUS-19237.
Повний текст джерелаDer CXC Chemokin‐Rezeptor 4 (CXCR4) und der atypische Chemokin‐Rezeptor 3 (ACKR3) sind heptatransmembranäre Rezeptoren, die in zahlreichen Krankheitsbildern eine Rolle spielen, wie in einigen Krebsarten. Beide Rezeptoren werden zwar von dem gleichen Chemokin CXCL12 aktiviert, allerdings mit unterschiedlichen Signalweiterleitungsmustern. Die Aktivierung von CXCR4 führt zu kanonischer GPCR Signaltransduktion über Gi‐Proteine und β‐Arrestine. Die Signalweiterleitung des Rezeptors ACKR3 hingegen, welcher hauptsächlich in intrazellulären Vesikeln vorliegt, erfolgt über ß‐Arrestinabhängige Signalwege. Es ist von großer Wichtigkeit die Dynamik und Kinetik dieser beiden Rezeptoren hinsichtlich der Aktivierung durch ihre Liganden und der Signalweiterleitung zu verstehen. In dieser Arbeit wurden verschiedene Förster‐Resonanzenergietransfer (FRET) Anwendungen kombiniert, um die frühen Phasen der Signal‐Kaskade von CXCR4 und ACKR3 zu untersuchen. Zur genaueren Aufklärung der Rezeptoraktivierung wurden intramolekulare FRET‐Sensoren entwickelt, hierzu wurden die Fluorophore Cyan‐fluoreszierendes Protein und engl. fluorescence arsenical hairpin binder verwendet. Die generierten Sensoren zeigten ähnliche funktionelle Eigenschaften wie die unveränderten Rezeptoren. Liganden‐induzierte Änderungen der Rezeptorkonformation können mittels dieser Sensoren beobachtet werden und stellen die ersten RET‐basierten Sensoren auf dem Forschungsgebiet der Chemokin‐Rezeptoren dar. Weitere FRET‐basierte Methoden wurden zur Untersuchung von Interaktionen zwischen Rezeptor und G‐Protein, Neuanordnung von Dimeren, sowie der G‐Protein Aktivierung eingesetzt und für beide Chemokin‐Rezeptoren etabliert. CXCR4 zeigte einen komplexen Aktivierungsmechanismus nach Stimulation durch CXCL12, bei welchem zunächst eine Neuordnung der Rezeptor‐Transmembrandomäne gefolgt von Neuordnungen zwischen Rezeptor und G‐Protein und zuletzt eine Neuordnung zwischen CXCR4 Protomeren erfolgte. Dies impliziert, dass im Aktivierungsprozess des Rezeptors Homodimere eine Rolle spielen. Zudem wurde eine verlängerte Gi ‐Protein Aktivierung gegenüber der Gq‐Protein Aktivierung bei CXCL12 stimuliertem CXCR4 beobachtet. Hingegen zeigte eine Stimulierung mit dem Macrophage Migration Inhibitory Factor (MIF) bei jedem Schritt der frühen Singal‐Kaskade veränderte Dynamiken und Kinetiken im Vergleich zu CXCL12. Darüber hinaus konnte keine Gi ‐Protein Aktivierung festgestellt werden. Dieser Befund zeigt individuelle Mechanismen für MIF und CXCL12 am CXCR4‐Rezeptor und liefert Belege für eine neuer Art von sequenziellen Signalweiterleitungen an GPCRs. Eine wichtige Beobachtung dieser Arbeit für eine potentielle Medikamentenentwicklung ist das CXCR4 ligandenunabhängige Aktivität zeigt. Um die Aktivierung des ACKR3 Sensors messen zu können wurde durch eine Co‐Transfektion mit K44A Dynamin eine höhere Membranständigkeit erreicht. CXCL12 und drei weiteren Agonisten zeigten am hier entwickelten ACKR3‐Sensor unterscheidbare Kinetiken. Mit diesem wertvollen Werkzeug können Liganden an diesem atypischen Rezeptor pharmakologisch charakterisiert werden. Es konnte keine CXCL12‐induzierte G‐Protein Aktivierung gemessen werden, trotz der stärkeren Präsenz an der Plasmamembran mit Hilfe der Dynamin‐Mutante. In Summe liefert diese Arbeit zum ersten Mal eine zeitliche Auflösung von Signalweiterleitungsmustern von zwei Chemokin‐Rezeptoren sowie wertvolle Werkzeuge zur Charakterisierung der frühen Phase der Signal‐Kaskade durch andere pharmakologisch relevanten Liganden
Montpas, Nicolas. "Étude du mode de liaison de l’antagoniste de CXCR4, TC14012, sur ACKR3 et évaluation de CXCR4 et d’ACKR3 comme marqueurs de survie de la leucémie pédiatrique dans un modèle murin xénogénique." Thèse, 2017. http://hdl.handle.net/1866/21464.
Повний текст джерелаHsieh, Mei-Lin, та 謝美玲. "非典型化學趨化素接受器ACKR3/CXCR7促進間質幹細胞所誘導出生後的血管新生與動脈形成". Thesis, 2016. http://ndltd.ncl.edu.tw/handle/5a7s46.
Повний текст джерелаBenredjem, Besma. "Identification des résidus essentiels à l’interaction du récepteur CXCR7 avec ses ligands SDF-1 et ITAC." Thèse, 2015. http://hdl.handle.net/1866/13662.
Повний текст джерелаChemokines are small secreted proteins whose major function is to stimulate the migration of immune cells to different organs and tissues. They are often involved in inflammatory and auto-immune diseases as well as cancers. Thus, chemokines and their G proteins Coupled Receptors (GPCR) are the pharmacological target of multiples molecules, currently tested in clinical trials. The model of our study is the atypical receptor CXCR7. This receptor is called atypical because it doesn’t signalize through the classical G protein pathway but rather signalizes through the β-arrestin pathway. CXCR7 is involved in many cancers, promotes metastatic progression and is a co-receptor for human immunodeficiency virus (HIV). However, there are, to date, no data concerning its binding mode to its ligands CXCL11/ITAC and CXCL12/SDF-1. We think that this information is crucial for the efficient development of agonists and antagonists and thus decided to identify the residus that are important for the binding of the two ligands of CXCR7 to the receptor and its subsequent activation. For that, we created a set of mutants by substitution or deletion of amino acids of the N-terminus, extracellular loops and transmembrane domains of the receptor. We then tested their surface expression by antibody staining and flow cytometry, their binding of the two ligands by binding assays and their capability to recruit β-arrestin in response to the ligands by BRET assays. The results obtained allowed us to identify important residues for the interaction of the systems CXCR7/SDF-1 and CXCR7/ITAC. They also suggest different binding modes of the chemokines ITAC and SDF-1 to CXCR7. Just like the binding of ITAC to its other receptor CXCR3, the binding mode of ITAC to CXCR7 follows the conventional two steps binding model of chemokine receptors. However, the binding of SDF-1 to CXCR7 follows another binding mode than the classical two step model, unlike its binding to its other receptor CXCR4.
Girard, Mélanie. "Dégradation de CXCL11 et CXCL10 par les lymphocytes T activés." Thèse, 2017. http://hdl.handle.net/1866/19417.
Повний текст джерелаDuring the immune response, T lymphocytes are activated in lymph nodes by antigen-presenting cells. Following activation, T cells up-regulate the chemokine receptor CXCR3, which allows them to infiltrate inflamed tissues by a migratory process named chemotaxis. To do so, CXCR3 allows the cells to detect concentration gradients of the chemokines CXCL11 and CXCL10 which are secreted locally, at the inflammation site. The chemokine gradient represents a directional cue, indicating to cells in which direction to migrate. Chemokine gradients must be regulated to assure an appropriate immune response. However, how these gradients are formed, maintained and eliminated is not well understood. It has been shown in other contexts that cells participate in gradient shaping. To do so, they express specialised chemokine receptors who scavenge chemokines, reducing chemokine levels in the environment. These receptors are considered atypical because they do not induce chemotaxis. In this work, we provide evidence for the regulation of the chemokines CXCL11 and CXCL10 that is in line with self-generation of chemokine gradients by chemotaxing activated T cells.