Dissertations / Theses: 'Protein-tyrosine kinases'

1

Gatesman, Ammer Amanda. "PKCalpha direct cSrc activation and podosome formation through the adaptor protein AFAP-110." Morgantown, W. Va. : [West Virginia University Libraries], 2004. https://etd.wvu.edu/etd/controller.jsp?moduleName=documentdata&jsp%5FetdId=3762.

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Thesis (Ph. D.)--West Virginia University, 2004
Title from document title page. Document formatted into pages; contains vii, 350 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 322-346).

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Holland, Pamela M. "Identification, interactions, and specificity of a novel MAP kinase kinase, MKK7 /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/9262.

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Wan, Yong. "Role of tyrosine kinases in G-protein signaling /." Access full-text from WCMC, 1997. http://proquest.umi.com/pqdweb?did=733008261&sid=12&Fmt=2&clientId=8424&RQT=309&VName=PQD.

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4

Gruszczyk, Jakub. "Structural analysis of bacterial protein tyrosine kinases (by-kinases) and their substrates." Paris 11, 2010. http://www.theses.fr/2010PA112135.

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Des tyrosine-kinases bactériennes atypiques (appelées BY-kinases) ont été identifiées comme constituant d'un complexe multiprotéique transmembranaire responsable de la synthèse et l'export des polysaccharides de la capsule bactérienne. Les BY-kinases s'autophosphorylent sur un cluster de tyrosine C-terminal et phosphorylent des protéines endogènes de la bactérie comme des UDP-sucres déshydrogénases impliquées dans la synthèse des précurseurs des exopolysaccharides. Les données structurales et fonctionnelles disponibles posaient la question de la conservation du degré d'oligomérisation et du mécanisme d'autophosphorylation entre BY-kinases de firmicutes et de protéobactéries. J'ai donc résolu la structure cristalline du domaine cytoplasmique de la BY-kinase Wzc de la protéobactérie E. Coli. Cette nouvelle structure montre que, comme la BY-kinase CapAB du firmicute S. Aureus, Wzc forme un anneau octamérique expliquant le mécanisme d'autophosphorylation intermoléculaire. Des mesures d'affinité par fluorimétrie m'ont également permis de montrer qu'une tyrosine interne Y569, initialement supposée réguler la trans-autophosphorylation du tyrosine-cluster, est directement impliquée dans la fixation du nucléotide. Nous montrons également qu'une boucle flexible riche en résidus basiques joue un rôle essentiel dans la synthèse de la capsule, probablement en interagissant avec d'autres protéines impliquées dans ce processus. De plus, j'ai résolu la structure cristalline de l'UDP-N-acétylmannosamine déshydrogenase CapO, substrat de la BY-kinase CapAB de S. Aureus. Cette structure révèle la formation d'un pont disulfure entre la cystéine catalytique C258 et le résidu C92 et la présence de potentiels sites de phosphorylation, Y89 et Y264, à proximité de ces deux cystéines. L'analyse de mutants est en cours afin d'élucider le mécanisme de régulation de cette enzyme. La comparaison avec les structures d'autres membres de cette famille de déshydrogénases permet également de mieux comprendre leur spécificité de substrat
Atypical bacterial tyrosine kinases (BY-kinases) have been identified as part of a multiprotein transmembrane complex responsible of the biosynthesis and export of capsular polysaccharides. BY-kinases autophosphorylate on a C-terminal tyrosine cluster and phosphorylate endogenous bacterial proteins like UDP-sugar dehydrogenases involved in the synthesis of exopolysaccharide precursors. Available structural and functional data raised the question of the conservation of the oligomerization state and of the autophosphorylation mechanism between BY-kinases from proteobacteria and firmicutes. I thus solved the crystal structure of the cytoplasmic domain of the BY-kinase Wzc from E. Coli. This new structure shows that, like the BY-kinase CapAB from the firmicute S. Aureus, Wzc forms an octameric ring explaining the intermolecular autophosphorylation mechanism. Fluorimetric affinity measurements further allowed me to show that the internal tyrosine Y569, initially supposed to regulate tyrosine-cluster trans-autophosphorylation, is directly involved in nucleotide binding. We also show that a flexible loop rich in basic residues plays an essential role in capsule synthesis, most probably through interaction with other proteins involved in this process. Moreover, I solved the crystal structure of UDP-N-acetylmannosamine dehydrogenase CapO, the substrate of the BY-kinases CapAB from S. Aureus. The structure reveals the formation of a disulfide bridge between the catalytic cysteine C258 and residue C92 and the presence of potential phosphorylation sites, Y89 and Y264, close to these two cysteines. Mutational analysis is underway in order to elucidate the regulatory mechanism of this enzyme. Comparison with the structures of other members of this family of dehydrogenases also allows us to shed light on their specific substrate recognition

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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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Lin, Xiaofeng. "Probing the regulatory mechanisms of protein tyrosine kinases, using C-terminal SRC kinase (CSK) as a model system /." View online ; access limited to URI, 2005. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3188064.

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7

Persson, Camilla. "Protein Tyrosine Phosphatases as Regulators of Receptor Ryrosine Kinases." Doctoral thesis, Uppsala University, Ludwig Institute for Cancer Research, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3345.

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Tyrosine phosphorylation is a crucial mechanism in cellular signaling and regulates proliferation, differentiation, migration and adhesion. The phosphorylation reaction is reversible and is governed by two families of enzymes: protein tyrosine kinases and protein tyrosine phosphatases (PTPs). This thesis investigates the role of PTPs in regulating receptor protein tyrosine kinases (RTKs), and explores a mechanism for regulation of phosphatase activity.

Most receptor tyrosine kinases are activated by ligand induced dimerization, which results in an increase in receptor phosphorylation. Preparations of ligand-stimulated dimeric PDGF β-receptors were shown to be less susceptible to dephosphorylation compared with unstimulated receptors. This revealed that reduced receptor dephosphorylation contributes to ligand-induced increase in RTK phosphorylation.

The receptor-like phosphatase DEP-1 site-selectively dephosphorylates the PDGF β-receptor. One of the most preferred sites is the PLC-γ binding phosphotyrosine pY1021, and the autoregulatory pY857 is one of the least preferred sites. By using chimeric phospho-peptides derived from these two sites as substrate for DEP-1, it was shown that a lysine residue at position +3 acts as a negative determinant for DEP-1 and that an aspartic acid residue at position –1 is a positive determinant.

The modulatory effect of TC-PTP on PDGF β-receptor signaling was explored by using mouse embryonic fibroblasts derived from TC-PTP knockout mice. PDGF β-receptors derived from knockout cells exhibited a higher level of ligand-induced phosphorylation compared to receptors from wildtype cells. The increase was unevenly distributed between different autophosphorylation sites. The PLC-γ binding site, previously implicated in chemotactic response, displayed the largest increase. Consistently, a cell migration assay revealed hyper-responsiveness to PDGF of TC-PTP knockout cells as compared to wildtype cells.

Reversible oxidation of the active site cysteine in PTPs is a mechanism, which have been postulated to regulate phosphatase specific activity. An antibody-based generic method for detection of oxidized PTPs was developed. Using this method it was revealed for the first time that UV-induced inactivation of PTPs involves oxidation of the active site cysteine.

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Kee, Nohjin. "Receptor protein tyrosine kinases in perinatal developing rat kidney." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0007/MQ44193.pdf.

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Kee, Nohjin. "Receptor protein tyrosine kinases in perinatal developing rat kidney." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=20260.

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We have identified receptor protein tyrosine kinases (PTKs) that are expressed and/or activated during kidney development. mRNA from fetal rat kidneys in late gestation (embryonic day 21), was used to prepare cDNA template for polymerase chain reaction amplification with primers based on conserved regions of PTKs, and products were subcloned and sequenced. Among 346 clones, we identified epidermal growth factor receptor (EGFr), Tie 2, platelet derived growth factor receptor (PDGFr)-alpha, PDGFr-beta, Flk-1, Flt-4, fibroblast growth factor receptor (FGFr)-1, FGFr-3, FGFr-4, Met, and RYK//Nbtk-1. PTK expression was studied by immunoprecipitation and immunoblotting of kidney membrane proteins with specific antibodies. EGFr, PDGFr-alpha, FGFr-1, FGFr-3, Met, and in some cases Tie-2 protein expression was greater in fetal kidneys, as compared with kidneys from 12 week adult rats, (controls). Flk-1, PDGFr-beta, and FGFr-4 proteins were expressed comparably; Flt-4 was not detected. As a reflection of receptor PTK activity, we assessed endogenous tyrosine phosphorylation, and in vitro autophosphorylation. EGFr and PDGFr-alpha displayed activity in fetal, but not adult kidneys. FGFr-3 and Flk-1 were active in some fetal kidneys; the other PTKs were not active. Thus, in late gestational rat kidney, there are distinct patterns of receptor PTK expression and activity. EGFr, PDGFr-alpha, FGFr-3 and Flk-1 are among PTKs that are activated, and they may mediate perinatal development of renal epithelial, interstitial, or vascular structures.

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Munawar, Munawar Ali. "The synthesis of novel inhibitors of protein tyrosine kinases." Thesis, Cardiff University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364476.

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Scales, Timothy M. E. "Tyrosine phosphorylation of tau protein by Src-family kinases." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406870.

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12

Lee, Daniel Cho-En. "Structural and functional studies of bacterial protein tyrosine kinases." Thesis, Kingston, Ont. : [s.n.], 2008. http://hdl.handle.net/1974/1521.

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Burns, Christopher John. "Tyrosine kinases and mitogen-activated protein kinases : roles in pancreatic Î²-cell function." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313990.

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14

Grabbe, Caroline. "Protein tyrosine kinases and the regulation of signalling and adhesion in Drosophila melanogaster /." Doctoral thesis, Umeå : Umeå University, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-971.

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15

Yang, Yaoming. "Regulation of protein tyrosine kinase ZAP-70 by serine phosphorylation." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=19442.

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The activation of the protein tyrosine kinase (PTK) ZAP-70 is fundamental to T cell receptor (TCR) signal transduction. TCR engagement induces raft-association of ZAP-70 and juxtaposes the cytoplasmic ZAP-70 with the raft-enriched Lck, which phosphorylates and activates ZAP-70. The active ZAP-70, cooperatively with Lck, initiates multiple intracellular pathways eventually leading to T cell activation and IL-2 production. Here, we describe the serine phosphorylation on ZAP-70 on the highly conserved S520DVWS524 motif, and investigate its role in coupling ZAP-70 with TCR signal transduction.

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Ford, Meredith Katherine. "Ischemic preconditioning of the myocardium, role of protein tyrosine kinases." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0022/MQ40863.pdf.

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Lee, Chia-Fang. "Analysis of the proteomic effects of leukaemic protein tyrosine kinases." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491484.

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There are a number of leukaemogenic protein tyrosine kinases (PTKs) associated with leukaemic transfonnation. Whilst each is linked with a specific disease their functional activity poses the question whether they have a degree of commonality in their effects upon target cells. Exon array analysis of the effects of 6 leukaemogenic PTKs (BCRJABL, TELIPDGFRp, FIPIIPDGFRa, D816V KIT, NPMlALK and FLT3ITD) revealed few common effects on the transcriptome. It is apparent, however, that proteome changes are not directly governed by transcriptome changes. Therefore, a new generation of eight channel iTRAQ reagent was applied to analyse the effects of these 6 leukaemogenic PTKs. Again these were found to have disparate effects on the proteome with few common targets. BCRJABL had the greatest effect on the proteome and had more effects in common with FIPIIPDGFRa. The only protein commonly affected by all six oncogenes was eosinophil-associated ribonuclease 7. Furthennore, correlation of the proteomics data with that from the exon microarray not only showed poor levels of correlation between transcript changes and protein level changes, but also revealed alternative patterns of regulation of the CAPG protein by different oncogenes, illustrating the utility of such a combined approach. The study was then focused on investigating the changes within the phosphoproteome. Due to the low stoichiometry of phosphorylation, some level of enrichment IS required. A method using phosphoprotein enrichment in conjunction with iTRAQ based mass spectrometry was developed using BalF3 and BCRJABL BalF3 cell lines. Following data validation, 27 significantly changing proteins were identified. The results revealed that more than half of the proteins showed statistically significant differences in phosphoprotein enrichment fractions remain unchanged in protein expression levels in whole cell lysates, including eIF4E. eIF4E has been found its phosphorylation status is critical in tumourgenesis. The data suggest this approach will be useful for the study of phosphorylation events.

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Zhang, Deyong, and 張德勇. "The regulation of cardiac potassium channels by protein tyrosine kinases." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41508294.

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Cunningham, Bernadette D. M. "Flavones and related compounds as inhibitors of protein tyrosine kinases." Thesis, Aston University, 1987. http://publications.aston.ac.uk/12513/.

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Aberrant tyrosine protein kinase activity has been implicated in the formation and maintenance of malignancy and so presents a potential target for cancer chemotherapy. Quercetin, a naturally occuring flavonoid, inhibits the tyrosine protein kinase encoded by the Rous sarcoma virus but also exhibits many other effects. Analogues of this compound were synthesised by the acylation of suitable 2-hydroxyacetophenones with appropriately substituted aromatic (or alicyclic) acid chlorides, followed by base catalysed rearrangement to the 1-(2-hydroxyphenyl)-3-phenylpropan-1,3-diones. Acid catalysed ring closure furnished flavones. The majority of the 1-(2-hydroxyphenyl)-3-phenylpropan-1,3-diones were shown by NMR to exist in the enol form. This was supported by the crystal structure of 1-(2-hydroxy-4-methoxyphenyl)-3-phenylpropan-1,3-dione. In contrast, 1.(4,6-dimethoxy-2-hydroxyphenyl)-3-phenylpropan-1,3-dione did not exhibit keto-enol tautomerism in the NMR spectrum and was shown in its crystal structure to assume a twisted conformation. Assessment of the biological activity of the analogues of quercetin was carried out using whole cells and the kinase domain of the tyrosine protein kinase encoded by the Abelson murine leukaemia virus, ptab150 kinase. Single cell suspension cultures and clonogenic potential of murine fibroblasts transformed by the Abelson Murine leukaemia virus (ANN-1 cells) did not indicate the existence of any structure activity relationship required for cytotoxicity or cytostasis. No selective toxicity was apparent when the `normal' parent cell line, (3T3), was used to assess the cytotoxic potential of quercetin. The ICS50 for these compounds were generally in the region of 1-100M. The potential for these compounds to inhibit ptab150 kinase was determined. A definite substitution requirement emerged from these experiments indicating a necessity for substituents in the A ring or in the 3-position of the flavone nucleus. Kinetic data showed these inhibitors to be competitive for ATP.

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Zhang, Deyong. "The regulation of cardiac potassium channels by protein tyrosine kinases." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41508294.

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21

Summy, Justin Matthew. "Functional domain contributions to signaling specificity between the non-receptor tyrosine kinases c-src and c-yes." Morgantown, W. Va. : [West Virginia University Libraries], 2001. http://etd.wvu.edu/templates/showETD.cfm?recnum=2239.

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Thesis (Ph. D.)--West Virginia University, 2001.
Title from document title page. Document formatted into pages; contains vi, 195 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 182-190).

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22

Zhao, Bailey. "Cloning and expression of protein tyrosine kinases in the medicinal leech." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1464872.

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Thesis (M.S.)--University of California, San Diego, 2009.
Title from first page of PDF file (viewed July 7, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 50-53).

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23

Wu, Jinzi. "Studies of substrate specificity, regulation and inhibition of protein-tyrosine kinases." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/282141.

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Protein tyrosine kinases (PTKs) play a crucial role in the regulation of cell proliferation, differentiation and signal transduction. However, substrate specificity and recognition motifs are not clear for most PTKs. Traditional methodologies for identifying substrate recognition motifs are often difficult and inefficient. In this dissertation, a novel approach for rapid discovery of linear substrate motifs of protein kinases has been developed using cyclic AMP-dependent protein kinase (cAPK) as a model system. This method is based on the screening of random synthetic combinatorial peptide libraries on beads where each bead expresses only one peptide entity. The peptide motif identified was RRXS, which exactly matched the motif for cAPK reported in the literature. Using this approach, a fraction of the random peptide library was screened for substrates of c-Src PTK. A heptapeptide, YIYGSFK, was identified and has been proven to be an efficient and specific substrate for c-Src PTK. A relatively specific pseudosubstrate-based peptide inhibitor of c-Src PTK has been developed based on the structure of YIYGSFK. Furthermore, a fraction of the octapeptide library was screened for substrates of c-Abl PTK. Fourteen peptides have been identified. Four different consensus sequences have been obtained by comparing the amino acid sequences of these peptides, suggesting that c-Abl PTK may have a relatively broad substrate specificity. Using these identified peptides as substrates, intrinsic tyrosine kinase activities of c-Abl and Bcr-Abl PTKs were compared. The data have suggested that Bcr sequences may directly activate the kinase activity of Abl protein. In addition, roles of the SH2 and SH3 domains in the regulation of the intrinsic kinase activity of Bcr-Abl have been studied. The results have indicated that the SH2 domain rather than SH3 domain was required for the intrinsic kinase activity of Bcr-Abl oncoprotein. In summary, the use of the combinatorial peptide library method has revealed some new insights on the substrate specificity and recognition motifs of PTKs, and suggested that small linear peptide motifs are important in the substrate recognition and phosphorylation by PTKs although the other factors may also contribute to the substrate specificity of PTKs.

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24

Mukhopadhyay, Archana. "Identification of a Low Molecular Weight Protein Tyrosine Phosphatase and Its Potential Physiological Substrates in Synechocystis sp. PCC 6803." Diss., Virginia Tech, 2006. http://hdl.handle.net/10919/26447.

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The predicted protein product of open reading frame slr0328 from Synechocystis sp. PCC 6803, SynPTP, possesses significant amino acid sequence similarity with known low molecular weight protein tyrosine phosphatases (PTPs). To determine the gross functional properties of this hypothetical protein, open reading frame slr0328 was cloned, and its predicted protein product was expressed in E. coli. The recombinant protein, SynPTP, was purified by metal ion column chromatography. The catalytic activity of SynPTP was examined toward several exogenous protein substrates that had been phosphorylated on either tyrosine residues or serine residues. SynPTP exhibited phosphatase activity toward tyrosine phosphorylated protein substrates (Vmax toward phosphotyrosyl 32P-casein was 1.5 nmol/min/mg). However, no phosphatase activity was detected toward serine phosphorylated protein substrates. SynPTP displayed phosphohydrolase activity toward several organophosphoesters including para-nitrophenyl phosphate (p-NPP), beta-napthyl phosphate and phosphotyrosine but not toward alpha-napthyl phosphate, phosphoserine, or phosphothreonine. Kinetic analysis indicated that the Km (0.6 mM) and Vmax (3.2 mmole/min/mg) values for SynPTP toward pNPP are similar to those of other known bacterial low molecular weight PTPs. The protein phosphatase activity of SynPTP was inhibited by sodium orthovanadate, a known inhibitor for tyrosine phosphatases, but not by okadaic acid, an inhibitor for many serine/threonine phosphatases. Mutagenic alteration of the predicted catalytic cysteine, Cys7, to serine abolished enzyme activity. Several phosphotyrosine containing proteins were detected from the whole cell extracts of Synechocystis sp. PCC 6803 through immunoreactions using anti-phosphotyrosine antibody. SynPTP was observed to dephosphorylate three of these proteins in vitro. Two of these proteins were identified by peptide-mass fingerprinting analysis, as PsaD (photosystem I subunit II) and CpcD (phycocyanin rod linker protein). In addition, several phosphotyrosine proteins were detected from the soluble and membrane fractions of Synechocystis sp. PCC 6803 cell extracts by in vitro substrate trapping as potential endogenous substrates of SynPTP. Two of these proteins were identified as the alpha and beta subunits of phycocyanin. We therefore speculate that SynPTP might be involved in the regulation of photosynthesis in Synechocystis sp. PCC 6803.
Ph. D.

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Lew, Gregory John. "Studies on protein phosphorylation in response to insulin in isolated cellular fractions reconstituted with insulin receptors." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/27979.

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The mechanism by which insulin and other polypeptide growth factors alter cellular metabolism is not fully understood. In the case of insulin, it is thought that phosphorylation/dephosphorylation mechanisms may play a central role in the signalling pathway. This is based on evidence which includes demonstration that the receptor for insulin is a tyrosine-specific protein kinase which is activated in response to insulin binding. Ultimately, insulin binding to its receptor on the surface of intact fat cells leads to altered levels of serine phosphorylation of several soluble proteins, including the phosphorylation of ATP-citrate lyase and acetyi-CoA carboxylase. Recently, studies involving site-specific mutagenesis have shown that the tyrosine kinase function of the insulin receptor is essential for insulin signalling. The studies described in this thesis have addressed the problem of how activation of the insulin receptor/tyrosine kinase results in the altered serine phosphorylation observed in intact cells in response to insulin. To gain further understanding of the cellular components required for insulin signalling, reconstitution experiments have been carried out mixing isolated cellular fractions with preparations of insulin receptors. The effects of insulin on altering protein-serine and protein-tyrosine phosphorylation have been determined in this reconstituted system. Results show that in a high-speed (100,000 x g) supernatant fraction prepared from rat adipose tissue endogenous protein-serine kinases are sensitive to conditions which are commonly employed for assaying insulin receptor/kinase activity. This includes inhibition by micromolar concentrations of MnCI₂, by 40 mM NaF, and by low reaction temperature (0°C). When the insulin receptor, present in a WGA-Sepharose-purified preparation of detergent-solublized rat liver membranes, was assayed in the complete absence of both MnCI₂ and NaF, receptor/tyrosine kinase activity was only slightly reduced with little or no decrease in the responsiveness to insulin. Furthermore, when the WGA-Sepharose-purified membrane fraction was incubated at 37°C in the presence of [ɣ -³²P]ATP several endogenous proteins were observed to be phosphorylated in addition to the β-subunit of the insulin receptor. These membrane proteins appear to be phosphorylated on tyrosine as indicated by their resistance to alkali hydrolysis. Upon reconstitution of the adipose tissue high-speed supernatant fraction with the WGA-Sepharose-purified preparation of insulin receptors the most striking effects observed were the phosphorylation of a 40 kd protein subunit (pp40) and the dephosphorylation of a 25 kd protein subunit (pp25) present in adipose tissue. The phosphorylation of pp40 occurs on tyrosine and is insulin-responsive, whereas the dephosphorylation of pp25 occurs following reconstitution with either untreated control, or insulin-activated insulin receptors. To assess the effect that reconstituted insulin receptors may have on the phosphorylation of endogenous ATP-citrate lyase in adipose tissue high-speed supernatant, it was found that a more pure preparation of insulin receptors was required. Further purification of the insulin receptor to homogeneity was therefore attempted using insulin-agarose affinity chromatography. However, difficulties including low yield and instability of the receptor through purification have prevented progress with these studies at present. In a separate study, highly purified acetyl-CoA carboxylase was reconstituted with a crude fraction consisting of total Triton-solublized membrane proteins. In this reconstituted system phosphorylation of acetyl-CoA carboxylase was enhanced to an extent greater than 6-fold after incubation with [ɣ -³²P]ATP. Following chromatography of the crude Triton-solublized extract over WGA-Sepharose this acetyl-CoA carboxylase kinase activity was found to be present in the flow-through void fraction and not in the N-acetylglucosamine eluted fraction. The acetyl-CoA carboxylase kinase, at present, does not appear to be insulin-responsive, but further studies are needed to confirm this observation.
Medicine, Faculty of
Biochemistry and Molecular Biology, Department of
Graduate

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26

Ayrapetov, Marina K. "Structural and functional studies of the Csk and Src family protein tyrosine kinases /." View online ; access limited to URI, 2006. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3225312.

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27

Crosby, David. "Cross-talk between tyrosine kinases and members of the protein kinase C family in human platelets." Thesis, University of Bristol, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288410.

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28

Briscoe, James. "JAKs, STATs and signal transduction in response to the interferons and interleukin-6." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336443.

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29

McDaid, John Patrick. "The role of protein tyrosine kinases in macrophage activation and cytokine responses." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411796.

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30

Fallah-Arani, Farnaz. "The role of Syk-family protein tyrosine kinases in B cell development." Thesis, Open University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424593.

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31

Gore, Martin John. "A molecular analysis of the Tyro3 subfamily of receptor protein-tyrosine kinases /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9735268.

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32

Griaud, François. "Proteomic analysis of leukaemogenic protein tyrosine kinase action." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/proteomic-analysis-of-leukaemogenic-protein-tyrosine-kinase-action(ff9d490b-5a94-45fc-a857-4f0826e4a11a).html.

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Introduction: Chronic myeloid leukaemia is a blood cancer which progresses from a chronic phase to an acute blast crisis if untreated. Disease progression and treatment resistance may be precipitated by the mutator action of BCR/ABL protein tyrosine kinase (PTK), but only few protein phosphosites involved in the DNA damage response have been investigated with respect to BCR/ABL action. Aim: The aim of this PhD project was to demonstrate that BCR/ABL PTK expression can affect the response to genotoxic stress signalling at the protein phosphorylation level. Methodology: Etoposide-induced DNA damage response has been studied in control and BCR/ABL PTK-expressing Ba/F3 cells using apoptosis and γH2AX assays. Quantitative phosphoproteomics was performed with iTRAQ peptide labelling to discover putative modulated phosphorylation sites. Absolute quantification (AQUA ) performed with selected reaction monitoring was used to validate discovery phosphoproteomics. The effect of genotoxic stress on the THO complex protein Thoc5/Fmip was studied using western blots. Results: The expression of BCR/ABL PTK induced γH2AX phosphorylation after etoposide exposure. This was associated with the modulation of H2AX tyrosine 142 phosphorylation, MDC1 (serines 595 and 1053) and Hemogen serine 380 phosphorylation among proteins regulated by both BCR/ABL PTK and etoposide. We identified that leukaemogenic PTKs mediate Thoc5/Fmip phosphorylation on tyrosine 225 via Src proto-oncogene and oxidative stress, while ATM and MEK1/2 may control its phosphorylation. Human CD34+ CD38- leukaemic stem cells showed pronounced level of THOC5/FMIP tyrosine phosphorylation. Expression of phosphomutant Thoc5/Fmip Y225F might reduce apoptosis mediated by etoposide and H2O2. Conclusion: BCR/ABL PTK can sustain, create, block and change the intensity of protein phosphorylation related to genotoxic stress. Modulation of H2AX, MDC1, Hemogen and Thoc5/Fmip post-translational modifications by BCR/ABL PTK might promote unfaithful DNA repair, genomic instability, anti-apoptotic signalling or abnormal cell differentiation, resulting in leukaemia progression.

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33

Sassatelli, Mathieu. "Synthèse de composés possédant un motif de type oxindole, inhibiteurs potentiels du récepteur de facteur de croissance de fibroblastes (FGFR1)." Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2005. http://tel.archives-ouvertes.fr/tel-00683658.

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Les facteurs de croissance et leurs récepteurs sont surexprimés dans un grand nombre de cancers et ont un rôle très important dans la prolifération cellulaire. Nous nous sommes intéressés aux inhibiteurs compétitifs de l'ATP du domaine tyrosine kinase des récepteurs de facteurs de croissance, plus particuliérement du FGFR1, l'un des quatre récepteurs à activité tyrosine kinase des facteurs de croissance de fibroblastes. Les interactions FGF/FGFR sont impliquées dans le développement tumoral et dans la stimulation de l'angiogénèse. Ce récepteur constitue donc une cible privilégiée pour le développement de nouveaux agents anticancéreux. Dans la première partie bibliographique, les différents facteurs de croissance et leurs récepteurs, ainsi que le rôle de leurs interactions spécifiques dans le cycle cellulaire sont décrits. Les principales familles d'inhibiteurs des récepteurs de facteurs de croissance sont ensuite détaillées. Afin de concevoir un nouveau modèle d'inhiteurs de l'activité tyrosine kinase de ces récepteurs, principalement du FGFR1, nous nous sommes orientés vers trois familles de composés. La synthèse de ces composés est présentée dans la deuxième partie. La troisième partie, présente une étude de docking (fixation du ligand dans le site de fixation de l'ATP de l'enzyme cible) et de minimisation d'énergie par mécanisme moléculaire des complexes de certains des composés synthétisés dans le site de fixation de l'ATP du FGFR1. Cette étude a été mise en oeuvre afin de voir si ces molécules pouvaient présenter une bonne affinité pour ce site. Les activités antiprolifératives sur différentes lignées cellulaires des nouveaux produits préparés au cours de ce travail ont été déterminées, ainsi que l'activité inhibitrice de certains produits sur diverses kinases. Ces résultats sont présentés dans la quatrième partie

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34

Wong, Chui-shan. "Transcriptional regulation of receptor tyrosine kinases AXL and MER in the testis /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31028081.

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35

Waters, Carrie Baird. "Involvement of tyrosine kinases in endothelin-1-induced contraction of porcine coronary arteries /." free to MU campus, to others for purchase, 1999. http://wwwlib.umi.com/cr/mo/fullcit?p9946309.

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36

Rivera, Reyes Brenda Mariola. "Regulation of the TCR signaling pathway." Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1132588714.

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37

Vernersson, Lindahl Emma. "Investigating the function of Anaplastic Lymphoma Kinase." Doctoral thesis, Umeå : Univ, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1956.

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Wong, Chui-shan, and 黃翠珊. "Transcriptional regulation of receptor tyrosine kinases AXL and MER inthe testis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B45015120.

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39

Waters, Carrie B. "Involvement of tyrosine kinases in endothelin-1-induced contraction of porcine coronary arteries." free to MU campus, to others for purchase, 1999. http://wwwlib.umi.com/cr/mo/fullcit?p9946309.

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40

Ippolito, Danielle Lorraine. "Regulation of G-protein gated inwardly rectifying potassium channels by tyrosine phosphorylation /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/6295.

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Wu, Wei, and 吴伟. "Regulation of hEAG1 and SK1 channels by protein tyrosine kinases and BK channels by cholesterol." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47029274.

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42

Kypta, Robert Martin. "The identification and characterisation of members of the src family of protein tyrosine kinases." Thesis, University College London (University of London), 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278797.

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43

Dietrich, Joanna Louise. "Phosphorylation of human platelet cytosolic phospholipase A₂ by the Src-family protein tyrosine kinases." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621659.

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44

Toerien, Lara K. Yurchak. "Role of palmitoylation in the biological function of Lck and Lyn protein tyrosine kinases /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9814552.

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45

Salsman, Scott J. "Redox regulation of protein tyrosine phosphatases in cell membrane receptor-mediated signal transduction." Oklahoma City : [s.n.], 2005.

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46

Zhou, Jie. "Functions of tyrosine kinases and phosphatases in presynaptic development during neuromuscular junction formation /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202007%20ZHOU.

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47

Telliez, Aurélie. "Etude du mécanisme d'action d'inhibiteurs de l'activité tyrosine kinase de l'EGFR sur des lignées cancéreuses prostatiques humaines." Lille 2, 2006. http://www.theses.fr/2006LIL2S037.

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A l'heure actuelle, le cancer de la prostate de pathologies non encore solutionnées par les traitements anticancéreux existants. Pour progresser dans la résolution de ce problème, en plus des thérapies hormonales et des agents cytotoxiques classiques, la recherche évolue vers de nouvelles stratégies thérapeutiques ciblant des facteurs indispensables à la prolifération et à la survie des cellules cancéreuses. Le récepteur de l'epidermal growth factor (EGF-R) est une protéine tyrosine kinase (PTK) jouant un rôle clé dans le développement des cellules et tissus normaux et présentant une activité augmentée dans un grand nombre de cancers, dont le cancer de la prostate. Différentes stratégies tendant à cibler les domaines extra- (anticorps, immunotoxines, ligands cytotoxiques) et intra- (inhibiteurs tyrosine kinase) cellulaires de ce récepteur ont été développées. Bien qu'il existe une grande homologie structurale entre les protéines tyrosine kinase au niveau du domaine intracellulaire assurant la liaison à l'ATP, plusieurs inhibiteurs TK sélectifs de l'EGF-R sont actuellement en essais cliniques. Parmi eux, l'Iressa* (ZD1839) a déjà montré son efficacité en monothérapie dans de nombreuses tumeurs solides (poumons, sein, prostate. . . ) et son utilisation en association avec une radiothérapie ou des agents cytotoxiques ciblant l'ADN est favorable. Cette 4-anilinoquinazoline présente cependant une toxicité pulmonaire non négligeable et semble être la cause de plusieurs décès par pneumonie interstitielle au Japon. Afin de limiter cette toxicité, le laboratoire a envisagé et synthétisé des analogues de l'Iressa* : éthers dissymétriques à noyau quinazoline (chaînes diéthylaminoéthoxy et n-butoxy en position 6 ou 7). L'objectif de mon travail a été de déterminer le mécanisme d'action de ces 4-anilinoquinazolines in vitro, sur des lignées cancéreuses prostatiques humaines hormonodépendantes (LNCaP) et hormonoindépendantes (PC3 et DU145). Après la mise au point d'une technique de dosage de l'activité TK de l'EGFR par marquage radioactif, l'activité des différents composés a été recherchée. Les propriétés de l'Iressaù et des analogues structuraux ont ensuite été déterminées sur différents paramètres cellulaires (prolifération, cycle cellulaire, survie et invasion). En plus des relations structure-activité qui ont été dégagées, les composés synthétisés ont montré un pouvoir proapoptotique et anti-invasif intéressant et supérieur au composé de référence. Afin de progresser dans la compréhension de leur mécanisme d'action, une analyse de puces à ADN, QPCR et western blot ont été menées et ont permis de déterminer l'impact des composés sur l'expression de certains gènes.

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48

Yamasaki, Sho. "Studies on the Regulation of T cell Receptor Mediated Signal Transduction by Protein Tyrosine Kinases." Kyoto University, 1999. http://hdl.handle.net/2433/181930.

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49

Dikic, Inga. "Signal Transduction by Proline-Rich Tyrosine Kinase Pyk2." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5316-3/.

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Kemble, David J. "A biochemical study on the regulation of the SRC and FGFR family of protein tyrosine kinases /." View online ; access limited to URI, 2009. http://0-digitalcommons.uri.edu.helin.uri.edu/dissertations/AAI3367994.

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Dissertations / Theses on the topic 'Protein-tyrosine kinases'

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