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Dissertations / Theses on the topic 'Receptor tyrosine kinase family'

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Published: 10 December 2022

Last updated: 29 January 2023

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1

Lorén, Christina. "Investigating the function of the Receptor Tyrosine Kinase ALK during Drosophila melanogaster development /." Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-411.

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2

Guiton, Michelle. "Molecular basis of signal transduction by the Trk family of receptor tyrosine kinases." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296366.

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3

KIM, SOYEON. "INVESTIGATING THE MOLECULAR INTERACTION OF ERBB RECEPTOR TYROSINE KINASES USING FLUORESCENCE CROSS CORRELATION SPECTROSCOPY." University of Akron / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=akron1632756640189756.

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4

Reschke, Markus Oliver. "Mitogen-inducible gene-6 is a negative regulator of the HER-family of receptor tyrosine kinases." kostenfrei, 2008. http://mediatum2.ub.tum.de/doc/654949/654949.pdf.

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5

Qi, Wenqing, Larry Cooke, Amy Stejskal, Christopher Riley, Kimiko Croce, Jose Saldanha, David Bearss, and Daruka Mahadevan. "MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer." BioMed Central, 2009. http://hdl.handle.net/10150/610342.

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BACKGROUND:Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/PI3K/Akt signaling axis has been implicated in prostate cancer development and progression. However, Erlotinib, an EGFR tyrosine kinase inhibitor, has less effect on proliferation and apoptosis in prostate cancer cell lines. In this study, we evaluate whether MP470, a novel receptor tyrosine kinase inhibitor alone or in combination with Erlotinib has inhibitory effect on prostate cancer in vitro and in vivo.METHODS:The efficacy of MP470 or MP470 plus Erlotinib was evaluated in vitro using three prostate cancer cell lines by MTS and apoptosis assays. The molecular mechanism study was carried out by phosphorylation antibody array, immunoblotting and immunohistochemistry. A LNCaP mouse xenograft model was also used to determine the tumor growth inhibition by MP470, Erlotinib or the combination treatments.RESULTS:MP470 exhibits low muM IC50 in prostate cancer cell lines. Additive effects on both cytotoxicity and induction of apoptosis were observed when LNCaP were treated with MP470 in combination with Erlotinib. This combination treatment completely inhibited phosphorylation of the HER family members (HER1, 2, 3), binding of PI3K regulatory unit p85 to HER3 and downstream Akt activity even after androgen depletion. Furthermore, in a LNCaP mouse xenograft model, the MP470-Erlotinib combination produced 30-65% dose-dependent tumor growth inhibition (TGI).CONCLUSION:We propose that MP470-Erlotinib targets the HER family/PI3K/Akt pathway and may represent a novel therapeutic strategy for prostate cancer.

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6

Beji, Abdelhamid [Verfasser], Kay Akademischer Betreuer] Schneitz, and Axel [Akademischer Betreuer] [Ullrich. "Significance of the Negative Regulator of HER Receptor Tyrosine Kinase Family, mig-6 Protein, in Colon Cancer and Glioblastoma / Abdelhamid Beji. Gutachter: Axel Ullrich. Betreuer: Kay Schneitz." München : Universitätsbibliothek der TU München, 2012. http://d-nb.info/1019590297/34.

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7

Goebel, Susan Michelle. "Phospho-regulation of hippocampal NMDA receptor localization and function /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.

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Thesis (Ph.D. in Neuroscience) -- University of Colorado Denver, 2007.
Typescript. Includes bibliographical references (leaves 200-233). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

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8

Zhao, Haotian. "Exploring the role of fibroblast growth factor (FGF) signaling in mouse lens fiber differentiation through tissue-specific disruption of FGF receptor gene family." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1072722841.

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Thesis (Ph. D.)--Ohio State University, 2004.
Title from first page of PDF file. Document formatted into pages; contains xii, 203 p.; also includes graphics (some col.) Includes bibliographical references (p. 179-203). Available online via OhioLINK's ETD Center

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9

Lennmyr, Fredrik. "Signal Transduction in Focal Cerebral Ischemia : Experimental Studies on VEGF, MAPK and Src family kinases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5267-1/.

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10

Ljuslinder, Ingrid. "Studies of LRIG1 and the ERBB receptor family in breast and colorectal cancer." Doctoral thesis, Umeå : Umeå university, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-25678.

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11

Fischer, Oliver Martin. "Receptor Tyrosine Kinase Activation in Human Carcinoma Cells." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-17997.

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12

Cheung, Man-ting, and 張敏婷. "Expression of met receptor tyrosine kinase in hepatocellularcarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B4669965X.

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13

Meyer, Sara. "The Ron Receptor Tyrosine Kinase in Tissue Morphogenesis." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1258666269.

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14

Thobe, Megan. "The Ron Receptor Tyrosine Kinase in Prostate Cancer." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273006729.

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15

Robertson, Sears Heather C. 1975. "The receptor tyrosine phosphatase Ptp69D and the receptor tyrosine kinase Pvr in Drosophila nervous system development." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/32254.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2004.
Includes bibliographical references.
Cell migration and axon guidance are highly similar processes important for the development of the nervous system. Both processes involve the transduction of signals across the membrane, resulting in changes in the cytoskeleton. I have examined the roles of two receptors that are involved in axon guidance and cell migration in Drosophila. Ptp69D is a receptor tyrosine phosphatase required for axon guidance in the developing embryo and for layer-specific axon targeting in the developing visual system. Using a dominant-negative form of Ptp69D, I have identified several genes with which Ptp69D genetically interacts in photoreceptor axon targeting. Removing a single dose of the cytoplasmic tyrosine kinases Src64 or Abl or the repulsive axon guidance receptor robo enhanced the Ptp69D dominant-negative phenotype. In mammalian systems, Src plays a key role in the regulation of cell adhesion, and Abl is a known regulator of actin cytoskeletal dynamics. Removing a single dose of the EGF receptor or Ras85D suppressed the Ptp69D dominant negative phenotype. Interestingly, the cytoplasmic tyrosine kinase PR2 binds Ptp69D, and the C. elegans homolog of PR2 has been found to suppress the Egfr/Ras pathway. Other evidence suggests that the Egfr/Ras pathway may be required for axon outgrowth. In addition to PR2, I also identified the receptor tyrosine kinase Pvr in a biochemical screen for proteins that bind Ptp69D. I generated mutants in Pvr by gene disruption and EMS mutagenesis. These mutants have disruptions in the embryonic central nervous system, including mispositioning of axon tracts and the glia that wrap them. However, these defects are not inherent to the CNS.
(cont.) Rather, they result from a failure of hemocytes to migrate out of the head and engulf dead cells in the CNS. To identify proteins that signal downstream of Pvr in cell migration, I used a yeast two-hybrid screen to identify 15 proteins that bind the intracellular domain of kinase-active Pvr. One of these proteins, drk, is required for Pvr-dependent Erk MAP kinase activation. None has defects in hemocyte migration when disrupted by RNA interference. Whether these proteins have redundant functions or function downstream of Pvr in other systems remains to be determined.
by Heather C. Robertson Sears.
Ph.D.

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16

Burgar, Helen Rachel. "Fibroblast growth factor receptor signalling." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275129.

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17

Fox, Gavin Connor. "Structural studies on MAP kinase phosphatases and the receptor tyrosine kinase TrkA." Thesis, Birkbeck (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268768.

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18

Doepfner, Kathrin T. "Targeting receptor tyrosine kinase signaling in acute myeloid leukemia /." Zürich, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253043.

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19

Paliouras, Grigorios. "Regulation of met receptor tyrosine kinase signalling and biology." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86661.

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Growth factor receptor tyrosine kinases (RTKs) are critical initiators of signal transduction pathways necessary for cell growth, differentiation, migration and survival. Many of these signals are coordinated through scaffold proteins that are phosphorylated upon their recruitment to the activated receptor complex. This provides binding sites for multiple proteins to activate and generate distinct biological responses. The amplitude and duration of a signal is regulated via dephosphorylation and degradation of target proteins. Signal regulation in this manner acts to promote the formation and disassembly of multi-protein complexes and diversify and localize signals downstream from RTKs.
The Met RTK and its ligand, hepatocyte growth factor (HGF), are positive regulators of epithelial morphogenesis, scatter, and survival. However little was known regarding the proteins responsible for attenuating Met receptor activation. In Chapter II, I demonstrated that the Met receptor was hyperphopshorylated in PTP1B-null mice in response to Fas-induced liver damage. Inhibition of Met signaling with PHA665752, removed protection from liver failure in PTP1B-null hepatocytes, demonstrating that PTP1B was a negative regulator of the Met RTK and its removal promoted cell survival against Fas-induced hepatic failure.
In response to Met receptor stimulation, the Gab1 scaffold protein is the prominent protein recruited and phosphorylated downstream from Met and is critical in mediating Met-dependent biological responses. In chapters III and IV, I identified the serine/threonine kinase Pak4 and the microtubule-bound guanine nucleotide exchange factor GEF-H1 as novel proteins recruited to Gab1 following Met receptor activation. I demonstrate that Gab1 and Pak4 synergize to enhance migration and invasion following HGF stimulation. Furthermore, the recruitment of Pak4 to Gab1 is important for its subcellular localization to lamellipodia and critical for epithelial cell dispersal and morphogenesis downstream from Met. In addition, GEF-H1 is important in focal adhesion formation and turnover and this correlates with the ability of GEF-H1 to promote epithelial migration and invasion downstream from Met.
Overall, these studies investigate molecular mechanisms regulating Met-dependent signals and demonstrate for the first time that the Met receptor is a substrate for PTP1B and identify Pak4 and GEF-H1 as key integrators of Met dependent cellular migration and invasion.
Les récepteurs tyrosine kinase aux facteurs de croissance sont des initiateurs critiques des voies de signalisation nécessaires à la croissance, la différentiation, la migration et la survie cellulaire. Beaucoup de ces signaux sont coordonnés par des protéines d'échafaudage qui sont phosphorylées au cours de leur recrutement au complexe de récepteurs activés. Ceci fournit des sites de liaison à de multiples protéines permettant l'activation et la génération de différentes réponses biologiques. L'amplitude et la durée d'un signal est régulée via la déphosphorylation et la dégradation des protéines cibles. De cette façon, la régulation du signal agit pour promouvoir la formation et le désassemblage de complexes protéiques et pour diversifier et localiser les signaux en aval des récepteurs tyrosine kinase.
Le récepteur Met et son ligand HGF (Hepatocyte Growth Factor) sont des régulateurs de la morphogenèse, la dispersion et la survie des cellules épithéliales. Toutefois, peu d'informations sont disponibles sur les protéines responsables de l'extinction des signaux issus du récepteur Met. Dans le chapitre II, je démontre que le récepteur Met est hyperphosphorylé dans les souris knock-out pour PTP1B en réponse aux dommages induits par Fas. L'inhibition par le composé PHA665752 de la signalisation par Met, relève la protection contre les crises hépatiques dans les souris KO pour PTP1B. Ceci démontre que PTP1B est un régulateur négatif de Met et son retrait permet la survie cellulaire contre les crises hépatiques induites par Fas.
En réponse à la stimulation du récepteur Met, la protéine d'échafaudage Gab1 est la plus importante des protéines recrutées et phosphorylées en aval de Met et cette protéine est critique dans la médiation des réponses biologiques dépendantes de Met. Dans les chapitres III et IV, j'ai identifié la kinase Ser/Thr Pak4 et le facteur d'échange de guanine lié aux microtubules (GEF-H1) en tant que nouvelles protéines recrutées à Gab1 suite à l'activation de Met. Je démontre que Gab1 et Pak4 agissent de façon synergique pour promouvoir la migration et l'invasion suite à la stimulation par HGF. De plus, le recrutement de Pak4 à Gab1 est important pour sa localisation cellulaire dans les lamellipodes et est critique pour la dispersion et la morphogenèse des cellules épithéliales en aval de Met. En outre, GEF-H1 est important pour la formation et le roulement des points d'adhésion focaux ce qui est en corrélation avec la capacité de GEF-H1 de promouvoir la migration et l'invasion épithéliale en aval de Met.
Ces études ont pour but d'investiguer les mécanismes moléculaires régulant les signaux dépendants de Met et démontrent pour la première fois que le récepteur Met est un substrat pour PTP1B. Finalement, Pak4 et GEF-H1 sont identifiés comme des intégrateurs clés de la migration et l'invasion cellulaire dépendante de Met.

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20

Park, Eun-Hee 1971. "Mechanisms of translation initiation of receptor tyrosine kinase Tie2." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102690.

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Angiogenesis is a process of new blood vessel formation and is the culmination of both mitogenic and tissue remodeling events, resulting in neovascularization. It is a physiological process that is required for, amongst others, normal embryonic development, female reproductive function, and wound healing. Angiogenesis is a tightly regulated process which is balanced by both positive and negative factors. However, in many disease states, including diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, and several cancers, dysregulation of angiogenesis contributes to disease progression. Previous published reports have implicated the coordinated activities of at least two families of receptor tyrosine kinases (RTKs), the vascular endothelial growth factor receptor (VEGFR) and the Tie receptor families, in this process.
Tie2, an endothelial-specific receptor tyrosine kinase, plays an essential role in normal blood vessel maturation, remodeling, and stability. Tie2 expression is also upregulated in various cancers indicating a role in tumor angiogenesis. The human Tie2 mRNA transcript contains an unusually long (372 nucleotides) 5' untranslated region (UTR) with five upstream open reading frames (uORFs). In this thesis, we demonstrate that the Tie2 5' UTR promotes cap-independent translation, indicating the presence of functional internal ribosome entry site (IRES). In addition, we illustrate that Tie2 IRES activity is maintained, and even slightly stimulated, under hypoxic conditions when cap-dependent protein synthesis is attenuated. We further show that the Tie2 IRES is functional during quiescence, another condition known to compromise cap-dependent translation. These results present how Tie2 mRNA is translated despite a cumbersome structured 5' UTR and how its production is secured under unfavorable environmental conditions.
We define experimental conditions where the Tie2 IRES is not active, allowing us to assess the contribution of cap-dependent translation to Tie2 protein synthesis. We demonstrate evidence that Tie2 mRNA can be translated via both cap-dependent scanning mechanism and internal initiation. Moreover, we show that the presence of the uORFs within the 5' UTR is inhibitory to downstream translation initiation. Our results suggest that the uORFs serve to decrease the proportion of ribosomes competent for reinitiation as they traverse the mRNA 5' UTR and thus minimizing interference with the IRES and/or mediating inefficient translation of the potent protein under normal conditions. Like many other cellular IRESes, the entire Tie2 5' UTR appears to be required for maximum IRES activity.
Taken together, our results underscore the complex mechanisms to control gene expression at the level of translation initiation of the Tie2 mRNA.

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21

O'Brien, Richard Mark. "Studies on the insulin receptor tyrosine-specific protein kinase." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252645.

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22

Wagner, Joel Patrick. "Multivariate studies of receptor tyrosine kinase function in cancer." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/81672.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 215-232).
Receptor tyrosine kinases (RTKs) are critical regulators of cellular homeostasis in multicellular organisms. They influence cell proliferation, migration, differentiation, and transcriptional activation, among other processes, and are therefore also relevant to cancer biology. Upon interaction with cognate ligand, RTKs initiate signaling cascades dependent in part on the phosphorylation of proteins. From a computational perspective, this thesis has studied methods for quantifying relationships between measured signals (using Bayesian network inference, correlation, and mutual information-based methods), and between signals and cellular phenotypes (using linear regression, partial least squares regression, and feature selection methods). From a biological perspective, this thesis has studied signaling between RTKs, signaling and cell migration downstream of RTKs in epithelial versus mesenchymal cell states, and comparative signaling across six RTKs. In the latter case, the results show that the six RTKs cluster into three classes based on their inferred signaling networks. Using publicly available transcriptional and pharmacological profiling data from hundreds of cancer cell lines, it was determined that expression of same-class RTK genes or their cognate ligands can correlate with insensitivity to drugs targeting other RTKs in that class. This suggests that resistance to RTK-targeted therapies in cancer may emerge in part because same-class RTKs can compensate for the reduced signaling of the inhibited receptor. The thesis concludes by quantitatively exploring the features of experimental data that improve model accuracy.
by Joel Patrick Wagner.
Ph.D.

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23

Veenstra, Cynthia. "The receptor tyrosine kinase Met and the protein tyrosine phosphatase PTPN2 in breast cancer." Doctoral thesis, Linköpings universitet, Avdelningen för kliniska vetenskaper, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-135047.

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Breast cancer is the most common form of cancer in women worldwide and the second leading cause of cancer death. It is a heterogeneous disease and is subdivided into different subtypes, all with different treatment responses and survival outcomes. Luminal breast cancers are characterised by the expression of oestrogen receptor and generally have a good prognosis. More aggressive tumours are marked by the presence of growth stimulating receptor tyrosine kinase HER2 (HER2-like breast cancer) or the absence of oestrogen receptor, progesterone receptor, and HER2 (triple-negative breast cancer,TNBC). The latter is the most aggressive form and is difficult to treat due to lack of treatment targets. This thesis aimed to explore possible prognostic and predictive biomarkers in different subtypes and study their role in breast cancer. To this aid, breast cancer tumours of pre- and post-menopausal patients enrolled in two cohorts were analysed for gene copy numbers and expression of proteins involved in cell proliferation. Gene copy numbers of receptor tyrosine kinases MET and EGFR, Met’s ligand HGF, and protein tyrosine phosphatase PTPN2 were determined by droplet digital PCR or quantitative PCR in both cohorts. Met, phosphorylated Met (pMet), HGF, and PTPN2 protein expression levels were analysed with immunohistochemical staining in the pre-menopausal cohort. Moreover,the role of the aforementioned proteins was investigated in breast cancer cell lines. Amplification of MET, HGF, and EGFR in breast tissues was found to be low (5-8%). These three genes, all located on chromosome 7, were found to be strongly correlated with eachother and to be associated with shortened distant recurrence-free survival. High protein expression of Met, pMet, and HGF was found in 33%, 53%, and 49% of the breast tumours. MET and EGFR were found to be more often amplified in TNBC disease, correlating with worse survival. Moreover, stromal expression of HGF was associated with shorter survival in TNBC. EGF stimulation in TNBC cell line MDA-MB-468 led to inhibited cell proliferation and migration. Partial knockdown of EGFR caused TNBC cells to proliferate and migrate more upon EGF treatment, mirroring EGFR inhibitor resistance. Knockdown of Met had in part the opposite effects, indicating that Met inhibitors might be useful in the treatment of TNBC. The increase in proliferation and migration upon EGFR depletion could be counteracted with simultaneous knockdown of EGFR and Met, indicating that dual inhibition of these proteins might be a future treatment option in TNBC. Copy loss of PTPN2 was reported in 15% of the cases in both pre- and post-menopausal cohorts. Low cytoplasmic PTPN2 protein expression was found in half of the cases. Loss of PTPN2 gene or protein was associated with a shorter distant recurrence-free survival in Luminal A and HER2-positive tumours, not in TNBC, suggesting a subtype-related prognostic value of PTPN2. Subtype relevance of PTPN2 was further implied by in vitro analyses. Whereas PTPN2 knockdown had no observed effect on TNBC cell lines, knockdown in the Luminal A cell line MCF7 inhibited Met phosphorylation and promoted phosphorylation of Akt, a key regulator of cellular proliferation and survival. The cell growth and survival regulating RAS/MAPK pathway remained unaffected. Knockdown in the HER2-positive cell line SKBR3 led to increased Met phosphorylation and decreased RAS/MAPK-related Erk phosphorylation as well as EGF-mediated transcription factor STAT3 phosphorylation. These results indicate that the role of PTPN2 in breast cancer is subtype-related and needs to be further investigated for future treatment options.

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24

Hocker, Samuel. "Receptor tyrosine kinase expression and phosphorylation in canine nasal carcinoma." Thesis, Kansas State University, 2018. http://hdl.handle.net/2097/38648.

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Master of Science in Biomedical Sciences
Department of Clinical Sciences
Mary Lynn Higginbotham
This study evaluated sixteen canine nasal carcinoma and five normal nasal epithelium samples for expression and phosphorylation of known targets of toceranib [vascular endothelial growth factor receptor-2 (VEGR2), platelet derived growth factor alpha (PDGFR-[alpha]), platelet derived growth factor receptor beta (PDGFR-[beta]), and stem cell factor receptor (c-KIT)] and epidermal growth factor receptor 1 (EGFR1) using immunohistochemistry, RT-PCR and a receptor tyrosine kinase (RTK) phosphorylation panel. Protein for VEGFR2 was expressed in neoplastic cells of all carcinomas, PDGFR-[alpha] was noted in 15/16, whereas PDGFR-[beta] was detected in 3/16 samples, but showed primarily stromal staining. Protein expression for c-KIT was present in 4/16 and EGFR1 was noted in 14/16 samples. Normal tissue showed variable protein expression of the RTKs. Messenger RNA for VEGFR2, PDGFR-[beta], and c-KIT were noted in all samples. Messenger RNA for PDGFR-[alpha] and EGFR1 were detected in 15/16 samples. All normal nasal tissue detected messenger RNA for all RTKs of interest. Constitutive phosphorylation of VEGFR2, PDGFR-[alpha], PDGFR-[beta] and c-KIT was not observed in any carcinoma or normal nasal sample, but phosphorylation of EGFR1 was noted in 10/16 carcinoma and 3/5 normal samples. The absence of major phosphorylated RTK targets of toceranib suggests the clinical effect of toceranib may occur through inhibition of alternative and currently unidentified RTK pathways in canine nasal carcinomas. The observed protein and message expression and phosphorylation of EGFR1 in the nasal carcinoma samples merits further inquiry into EGFR1 as a therapeutic target for this cancer.

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25

Vearing, Christopher John, and chris vearing@med monash edu au. "Structure, function & control of the EphA3 receptor tyrosine kinase." Swinburne University of Technology, 2005. http://adt.lib.swin.edu.au./public/adt-VSWT20051017.094940.

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The implication of the transmembrane signalling Receptor Tyrosine Kinases (RTKs) in cancer has accelerated the pursuit for drugs to target these molecules. In the process our understanding of how these membrane bound molecules are entangled in cell signalling has significantly expanded. There is now evidence that RTKs can facilitate the formation of a lattice-type network of signalling molecules to elicit whole cell responses to external ligand stimuli. Although beginning to be unravelled, knowledge pertaining to the mechanisms of molecular control that initiate these signalling pathways is still in its infancy. In this thesis, a random mutagenesis approach allowed the identification of the crucial interaction surfaces between membrane-bound EphA3 and its preferential binding partner ephrinA5, that are required to induce the formation of higher-order Eph signalling complexes. Modelling and experimental dissection of this co-ordinated receptor aggregation has provided detailed insights into the molecular mechanisms of Eph receptor activation, which in some aspects may also apply to other members of the RTK family. In particular, the importance of certain molecular interfaces in determining preferential and non-preferential Eph/ephrin interactions, suggests their role in the selection of biologically important binding partners. In addition to the assignment of the ephrin-interaction surfaces, the random mutagenesis strategy also identified a continuous conformational epitope as binding site for an anti-EphA3 monoclonal antibody. Fortuitously, antibody binding to this site functionally mimics ephrin stimulation of EphA3 positive cells, and in particular together with divalent ephrinA5, yields synergistically enhanced EphA3 activation. Elucidation of the underlying mechanism has provided opportunities to develop an efficient EphA3 targeting mechanism that is based on increased affinity and accelerated ephrinA5 uptake as consequence of this unique activation mechanism. On a genetic level, novel oligonucleotide analogues known as Peptide Nucleic Acids (PNAs) were analysed for their ability to sterically inhibit EphA3 DNA transcription and suggest a dosedependent downregulation of EphA3 expression, in malignant melanoma cells. Combined, ephrinA5, the anti-EphA3 MAb (IIIA4) and PNA, offer the possibility to investigate the specific machinery involved in Eph receptor expression and signalling for the specific targeting of EphA3 expressing tumour cells.

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26

Edling, Charlotte. "Receptor tyrosine kinase c-Kit signalling in hematopoietic progenitor cells." Doctoral thesis, Umeå : Umeå University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-888.

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27

Coonan, Jason R. "Regulation of neural connectivity by the EphA4 receptor tyrosine kinase /." Connect to thesis, 2001. http://eprints.unimelb.edu.au/archive/00000727.

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28

Schuller, Annika Corinna. "Protein recruitment to receptor tyrosine kinase-mediated early signalling complexes." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445051/.

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Receptor tyrosine kinase (RTK) signalling regulates the activation of numerous cellular processes in response to various external stimuli. Spatio-temporal regulation of protein recruitment to activated tyrosine kinase receptors is important for the generation of specific cellular responses to various external stimuli. The involvement of the signalling proteins She, FRS2, Grb2 and Sos and the formation of distinct signalling complexes downstream of three RTKs (TrkA, EGFR, FGFR) was assessed to analyse their role in maintaining signalling specificity. All four signalling proteins played a role in TrkA, EGFR and FGFR signalling, but their recruitment to and involvement in signalling complexes varied depending on the stimulus. The observations indicated that formation of unique multiprotein assemblies provides a mechanism for different receptors to elicit specific signals despite employing the same signalling proteins. Detailed analysis of She recruitment to the FGFR2 revealed co-localisation and co-precipitation with the receptor but no direct interaction. This finding provided additional insight into how the availability of binding sites on different receptors regulates the recruitment of individual proteins to receptor-specific signalling complexes. Secondly, the effects of mutations in the FGFR2 extracellular region on protein recruitment to the receptor and its overall signalling specificity were investigated. Two substitution mutations in the FGFR2, which cause Apert syndrome, result in increased affinity of FGFR2 for FGF. Detailed analysis of the FGFR2 itself and signalling from it in the presence of these mutations indicated that they also result in altered receptor glycosylation, phosphorylation and glycosaminoglycans dependency as well as enhanced Erkl/2 activation. Additionally, recruitment and phosphorylation of She were altered in cells expressing the Apert syndrome mutations. The effects of the mutations on the FGFR2 and the signalling complex formed profoundly altered FGFR2-induced signals and cellular responses. These findings highlight the importance of retaining the integrity of protein recruitment and signalling complex formation to achieve signalling specificity.

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29

李震威 and Chun-wai Davy Lee. "RET receptor tyrosine kinase in developing, adult and polycystic kidneys." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31241931.

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30

Reynolds, Andrew Robert. "Functional fluorescence imaging of receptor tyrosine kinase activity in cells." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398898.

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31

Goodman, K. M. "RET receptor tyrosine kinase architecture, protein interactions and chemical inhibition." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1380777/.

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The RET receptor tyrosine kinase plays a major role in embryonic and adult vertebrate development. Deregulation of RET signalling leads directly to multiple human diseases. Like many receptor tyrosine kinases, the intracellular tyrosine kinase domain of RET is activated by binding of ligand/co-receptor to its ectodomain (ECD). RET is unique among receptor tyrosine kinases, possessing cadherin-like domains (CLD1–4) within its ECD. This thesis describes the architecture of the RET-ECD elucidated using small- angle X-ray scattering (SAXS). These data reveal the interdomain angles and non- linearity of the four CLDs, as well as the location of the membrane-proximal cysteine rich domain (CRD) packed against CLD4. I use this SAXS-derived model of the RET- ECD together with published crystal structures of a RET ligand and co-receptor, to fit into a negative stain electron microscopy 3D reconstruction of a mammalian ligand/co- receptor/RET-ECD ternary complex. The resulting preliminary pseudo-atomic model contains a two-fold symmetrical RET ternary complex with two RET-ECDs wrapped around a core ligand/co-receptor, making extensive contacts from both the N-terminal CLD1–3 region and the membrane-proximal CRD consistent with previous biochemical data and our antibody-epitope mapping. This thesis describes the first view of the RET- ECD and the ligand/co-receptor/RET ternary complex architecture, with important implications for Hirschsprung’s disease and for understanding how ligand-independent RET activation occurs in type 2 multiple endocrine neoplasias.

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Aubertin, Johannes. "Characterization of receptor tyrosine kinase signaling pathways in bladder cancer." Paris 11, 2009. http://www.theses.fr/2009PA11T047.

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Lee, Chun-wai Davy. "RET receptor tyrosine kinase in developing, adult and polycystic kidneys." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23273732.

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Wong, Wai-lap. "Signal transduction pathways of ret receptor tuyrosine kinase." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B22786478.

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王偉立 and Wai-lap Wong. "Signal transduction pathways of ret receptor tuyrosine kinase." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31225354.

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36

Chan, Richard Muller William J. "In vivo structure-function studies of the ErbB2 receptor tyrosine kinase /." *McMaster only, 2004.

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37

Shulman, Johanna. "Biochemical analysis of activating mutations of the kit receptor tyrosine kinase." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0003/MQ40794.pdf.

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38

So, Wai Kin. "Role of receptor tyrosine kinase regulator Sprouty in ovarian cancer cells." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42242.

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Aberrant epidermal growth factor receptor (EGFR) activity contributes to the development of epithelial ovarian cancer (EOC), a common and lethal female malignancy. Elucidating the regulation of EGFR function will improve treatments for EOC and the survival of patients. This study aims to elucidate the role of Sprouty (SPRY) proteins, which are EGFR regulators, in EOC. The investigation began with demonstrating the downregulation of mRNA levels of two SPRY members, SPRY2 and SPRY4, in EOC tissues and/or cell lines. Deletion of the SPRY2 gene was found to cause reduced SPRY2 mRNA. Loss of the SPRY2 gene and thus its expression are particularly common in high-grade serous tumors, suggesting that SPRY2 deficiency may be involved in the pathogenesis of this prevailing subtype of EOC. The regulatory mechanisms of SPRY level are incompletely understood. The EGFR ligand EGF strongly upregulates SPRY4 protein level primarily through the ERK pathway. In addition, the PI3K/AKT pathway and hypoxia-inducible factor-1 (HIF-1α) have been shown to be involved in SPRY4 regulation, allowing the possibility that SPRY4 is regulated by micro-environmental (hypoxia) and genetic (PI3K mutation) abnormalities. Functionally, SPRY2 and SPRY4 counteract various aspects of EGFR activity and generally have tumor suppressor functions. First, in contrast to the EGFR, SPRY2 and SPRY4 prevent loss of cell adhesion by E-cadherin and therefore suppress cancer cell invasion. Second, SPRY4 inhibits PI3K/AKT signalling activated by EGF, as AKT activation is enhanced in the absence of SPRY4. Finally, the HIF-1α oncogene has been identified as a novel SPRY4 target. In ovarian cancer cell lines, SPRY4 suppresses the basal and EGF-stimulated expression of HIF-1α. The negative effects of SPRY4 on HIF-1α are also reflected by modulation of HIF-1 activity and target gene expression. SPRY4 has also been shown to destabilise HIF-1α protein, independent of the classic HIF-1α degradation pathway. The current study investigated the expression, regulation and function of SPRY in ovarian cancer. Understanding the tumor suppressor role of SPRY will not only enhance our knowledge about the pathophysiology of ovarian cancer but also identifies a possible therapeutic intervention against this lethal malignancy.

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Petkiewicz, Stephanie L. "The Met receptor tyrosine kinase in mammary gland tumorigenesis and development /." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103278.

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The Met receptor tyrosine kinase (RTK) is expressed in the mammary gland under both normal and neoplastic conditions. Overexpression of the Met receptor is found in 15--20% of human breast cancers and is correlated with shortened disease-free interval and overall survival. In order to explore the role of dysregulated Met receptor signaling on the development of mammary tumors I have characterized a transgenic mouse model that expresses either wild type or a dysregulated Met receptor in the mammary epithelium under the control of the mouse mammary tumor virus promoter/enhancer (MMTV-Met). The Met receptor variants contained a mutation that results in decreased receptor ubiquitination and prolonged receptor signaling (Y1003F) or an activating mutation that was originally observed in patients with papillary renal carcinoma (M1250T) or both mutations (YF/MT). In vitro and in vivo transformation assays demonstrated that each mutation singly is weakly transforming, however, there was an additive effect on transformation when both mutations were present. This additive effect was observed in the transgenic mice where multiparous MMTV-Met-YF/MT mice developed tumors earlier and with much greater penetrance than did mice expressing either of the single mutants. This provides the first in vivo model that demonstrates a role for ubiquitination in suppression of transforming activity of an RTK. MMTV-Met-YF/MT tumors displayed a range of histological phenotypes but were mainly comprised of luminal lineage cells. Notably, MMTV-Met-M1250T tumors contained cells from both the basal and luminal populations, suggesting transformation of a progenitor cell. Progenitor cell transformation in RTK transgenic mouse models is uncommon and highlights distinct signaling differences and potentially lineage specificity of the two Met mutants.
Through assays of overexpression in vivo and inhibition in vitro, Met receptor signaling has been correlated with the development of the mammary gland. To examine the effects of loss of Met receptor signaling on mammary gland development I have utilized the Cre/LoxP1 recombination system to knock-out the Met receptor from the mammary epithelium. Mammary-specific Cre recombinase efficiently excised floxed DNA as visualized by activation of a beta-galactosidase reporter In Met+/+ glands, however, few beta-galactosidase positive cells are retained In the Mefl/fl glands and an intermediate number are retained in the Met fl/+ glands. This indicates that Met-null cells are selected against and supports a role for Met in the development of the mammary gland.

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Luzac, Michal Leonie. "Small Molecules as Potential Inhibitors of the Met Tyrosine Kinase Receptor." Thesis, University College London (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498510.

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Irving, Carol. "Characterisation of the receptor tyrosine kinase, Sek-1, during vertebrate embryogenesis." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263644.

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Girlalt-Pujol, Marta. "Investigating the regulation of the endocytosis of tyrosine kinase receptor Tie2." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/18527/.

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Tie2 receptor is a cell surface tyrosine kinase receptor expressed almost exclusively in endothelial cells, where it is mainly studied for its role in angiogenesis. Indeed, Tie2 has been related to various pathologies with vascular implication such as pulmonary hypertension, diabetes retinopathy and tumour growth. The regulation of Tie2 activation and function is complex, involving multiple factors that are still being investigated. For instance, after activation by the agonistic ligand Angiopoietin-1 (Ang1), Tie2 is internalized in cells by an endocytic mechanism that has yet to be fully characterised. As it has been shown that endocytosis of molecules can play a regulatory role in intracellular signalling in various ways I believe that the endocytosis of Tie2 may also be important in the regulation of its activity and cellular output. Therefore, I decided to characterise the endocytic mechanisms involved in the internalization of Tie2 to determine whether endocytosis can be a regulator of Tie2 signalling. To facilitate the study of Tie2 I created a HeLa cell line with inducible expression of a Tie2FLAG receptor that emulates both expression levels and characteristics of endogenous Tie2 in Human Umbilical Vein Endothelial Cells. To study the endocytosis of Tie2 receptor I developed an immunofluorescence-based assay to quantify the amount of internalized agonistic ligand Ang1 in a high throughput Screening format. I also performed complementary immunofluorescence and western blot analysis to investigate the characteristics of Tie2 internalization.

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McCarthy, Mark John. "Studies on the endothelial cell specific receptor tyrosine kinase, tie-1." Thesis, University of Leicester, 1999. http://hdl.handle.net/2381/34159.

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Tie-1 is an endothelial cell specific tyrosine kinase receptor that is essential for the stabilisation of newly developed vessels and maintenance of endothelial cell integrity in the latter stages of angiogenesis. There is presently no known ligand for the tie-1 receptor, little is known of the factors that regulate its expression and information is lacking on downstream signalling events that occur following its activation. This study demonstrates that tie-1 protein expression in endothelial cells is increased at the level of transcription by VEGF and low oxygen tension, factors which are known to initiate angiogenesis. The cell surface expression of the receptor is also regulated by a metalloprotease enzyme which results in tie-1 ectodomain cleavage at a region close to the transmembrane region. This event generates a tie-1 endodomain fragment that persists in the cell membrane for several hours. This results in downstream signalling events, which lead to further secretion of the metalloprotease enzyme that can cleave tie-1 ectodomain in surrounding endothelial cells. The cleavage event may well be protein kinase C dependent and can be activated by VEGF. The loss of the extracellular domain of tie-1 inhibits tie-1 ligand binding at the cell surface and probably results in destabilising the endothelial cell allowing it to undergo angiogenesis or vessel remodelling. A potential tie-1 ligand, produced by a malignant melanoma cell line, results m activation of the tie-1 receptor by autophosphorylation of tyrosine kinase residues. Attempts at isolation of this protein suggest that it is a glycoprotein with a molecular weight of approximately 60-90kDa and this protein has been visualised on a nitrocellulose membrane and is currently awaiting N-terminal sequencing. Work presented in this thesis demonstrates for the first time factors that regulate expression of tie-1, novel downstream signalling events and the possible isolation of the tie-1 ligand.

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Myers, Samuel Harry. "Development of novel receptor tyrosine kinase inhibitors by a chemocentric approach." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28769.

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In recent years, there has been a major movement in the pharmaceutical industry towards the development of molecules that selectivity inhibit a previously-validated specific target. This is referred to as target-based drug discovery. It was hoped that adopting this approach would usher in a new golden age of drug discovery. However, this has not been the case, with issues arising such as the target’s mechanism of action being poorly understood, with it not playing the expected role in the disease progression, or feedback resistance mechanisms causing the target to lose its role in the disease. In contrast to this, in the past 20 years it has been argued that developing drugs in a target-agnostic way and screening them against an expressed phenotype i.e. phenotypic drug discovery, has been more successful, despite fewer programs being run in the manner. The AXL kinase is a receptor tyrosine kinase (RTK) and a member of the TAM family, along with MER and TYRO3. AXL has long been associated with numerous types of cancer. Having been first discovered in 1991 in acute myeloid leukaemia (AML), it has gone on to be more associated with advanced solid tumours such as brain, breast, and lung, with the trend being that increased AXL correlates with a poorer prognosis for the patient. Upon the activation of AXL by the vitamin K ligand GAS6, a series of downstream pathways are activated that go on to encourage cell survival, proliferation, and migration. In addition to this, AXL has been shown to be involved in crosstalk with other kinase pathways, resulting in AXL expression being associated with chemoresistance and survival mechanisms. Despite the promising outlook for AXL inhibitors, to date only one selective AXL inhibitor, BGB324 (formally R428) has entered clinical trials, with selective AXL inhibitors being difficult to develop due to a lack of a crystal structure or a reliable homology model. To address the aforementioned issues that target-based approaches can suffer from, and due to AXL lacking a crystal structure, the work in this thesis utilised a pragmatic drug design method that started from ligands/existing scaffolds known to inhibit the target from the literature (publications, clinical trials and patents). A series of small libraries were prepared and then tested against a selected phenotype e.g. cell viability, in at least two cell types: one that expressed the target (e.g. AXL) and one that did not. Hits were optimised for potency against the desired phenotype. The compounds then went through target deconvolution (kinase screening) to confirm the target of the inhibitors. Employing this approach, we initially synthesised two small libraries of potential AXL inhibitors. The potency of these compounds was tested using cell-based phenotypic assays, by evaluating cell viability in both native and chemo-resistant breast cancer cells. These libraries were optimised through focused combinatorial synthesis and phenotypic screening, to yield a small collection of antiproliferative hits. These hits were then profiled against a panel of twelve select kinases. The first library, while giving some important structural information, did not inhibit the kinases screened in a meaningful manner. However, the second library gave several potent compounds, inhibiting AXL, FLT3, and RET, with one compound being selective for AXL. The leads from this series were optimised further, through SAR studies, gaining important structural information in order to improve potency and selectivity of the compounds. The flexibility of the phenotypic cell-based approach allowed the pursuit of FLT3 inhibitors, resulting in the synthesis of one of the most potent FLT3 inhibitors synthesised to date.

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Tuzi, Nadia Lucia. "The Eph growth factor receptor." Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294878.

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Lam, Hiu-chor, and 林曉初. "Functional characterization of tyrosine phosphatase non-receptor 21, anovel modulator of ErbB4/NRG3." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44229288.

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Lam, Hiu-chor. "Functional characterization of tyrosine phosphatase non-receptor 21, a novel modulator of ErbB4/NRG3." Click to view the E-thesis via HKUTO View the Table of Contents & Abstract, 2010. http://sunzi.lib.hku.hk/hkuto/record/B44229288.

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48

Paluch, Andrew M. "The Ron Receptor Tyrosine Kinase as a Mediator of Inflammation and Tumorigenesis." University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1455208865.

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49

Zhao, Tong Tong. "Mechanism and Therapeutic Potential of Statin-Mediated Inhibition of Tyrosine Kinase Receptors." Thesis, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20334.

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Receptor tyrosine kinases (RTK) are key regulators of growth, differentiation and survival of epithelial cells and play a significant role in the development and progression of cancers derived from these tissues. In malignant cells, these receptors and their downstream signalling pathways are often deregulated, leading to cell hyper-proliferation, enhanced cell survival and increased metastatic potential. Furthermore, endothelial expressed RTKs regulate tumor angiogenesis allowing for tumor growth and maintenance by promoting their vascularization. Epithelial malignancies such as squamous cell carcinomas (SCC), non-small cell lung (NSCLC) and malignant mesotheliomas have very limited treatment options when presenting as metastatic disease. RTKs, particularly the epidermal growth factor (EGFR) and the vascular endothelial growth factor (VEGFR) receptors, have been shown to play significant roles in the pathogenesis of these tumor types. Statins are potent inhibitors of HMG-CoA reductase, the rate limiting enzyme of the mevalonate pathway, that are widely used as hypercholesterolemia treatments. The mevalonate pathway produces a variety of end products that are critical for many different cellular pathways, thus, targeting this pathway can affect multiple signalling pathways. Our laboratory has previously shown that lovastatin can induce tumor specific apoptosis especially in SCC and that 23% of recurrent SCC patients treated with lovastatin as a single agent showed disease stabilization in our Phase I clinical trial. Subsequently, our lab was able to demonstrate that lovastatin in combination with gefitinib, a potent inhibitor of the EGFR showed co-operative cytotoxicity when combined (Chapter 2). Furthermore, the pro-apoptotic and cytotoxic effects of these agents were found to be synergistic and to be manifested in several types of tumor cell lines including SCC, NSCLC and glioblastoma. I was able to expand upon these important findings and demonstrated that lovastatin, through its ability to disrupt the actin cytoskeleton, inhibited EGFR dimerization and activation (Chapter 3). This novel mechanism targeting this receptor has clinical implications as lovastatin treatment combined with gefitinib showed co-operative inhibitory effects on EGFR activation and downstream signalling. The RTK family of proteins share similar features with respect to activation, internalization and downstream signalling effectors. I further demonstrated that lovastatin can inhibit the VEGFR-2 in endothelial cells and mesotheliomas, where VEGF and its receptor are co-expressed driving their proliferation, and induces synergistic cytotoxicity in mesothelioma cells in combination with VEGFR-2 tyrosine kinase inhibitors (Chapter 4). These findings suggest that statins may augment the effects of a variety of RTK inhibitors in a similar fashion representing a novel combinational therapeutic approach in a wide repertoire of human cancers. More importantly, based on this work, we initiated a Phase I/II study evaluating high dose rosuvastatin and the EGFR inhibitor tarceva in SCC and NSCLC patients at our institute. This clinical evaluation will provide invaluable data that will play a role in developing this novel therapeutic strategy. Together, the work embodied in this thesis provides a model for the regulation of EGFR/VEGFR-2 activation and signalling by targeting the rho family of proteins that demonstrates a novel mechanism that can be exploited to refine current therapeutic paradigms.

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Hantschel, Oliver. "Structural and functional analysis of the non receptor tyrosine kinase c-Abl." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=970379552.

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