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Characterization of calcium signals during the blastula period of zebrafish (danio rerio) embryogenesis /Ma, Leung Hang. January 2007 (has links)
Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2007. / Includes bibliographical references (leaves 213-239). Also available in electronic version.
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Altered regulation of PTEN by mutagenesis and p85 bindingPastor, M Chris 19 August 2008
Growth and proliferation are normal functions of cells mediated in part via receptor tyrosine kinases such as the epidermal growth factor (EGF) receptor (EGFR). The EGFR binds the extracellular signaling ligand EGF and transduces the signal into the cell. Phosphatidylinositol 3'-kinase (PI3K) responds to EGFR activation and initiates downstream signaling cascades responsible for cell cycle entry, proliferation and inhibition of apoptosis. Cell cycle arrest is required to stop cell growth and proliferation as well as allow apoptosis, if required. The phosphatase and tensin homologue deleted on chromosome ten (PTEN) directly opposes PI3K signaling since its substrate is the PI3K product phosphatidylinositol 3,4,5-trisphosphate. PI3K is a heterodimer composed of a p85 regulatory subunit and a p110 catalytic subunit. PTEN is an essential tumor suppressor protein. Absence of PTEN has been associated with several types of cancer. <p>Our laboratory has characterized new specialized functions for the p85 protein. One function discovered was the ability of p85 to enhance PTEN lipid phosphatase activity. In this thesis PTEN activity is shown to be enhanced at least 3.5 fold in vitro by an equimolar amount of p85. <p>We performed an analysis of PTEN using seven PTEN mutants. Two types of mutants were created: i) regulatory or possible regulatory phosphorylation sites were substituted to mimic both phosphorylated and non-phosphorylated states and ii) alanine substitution of basic amino acid residues. The phosphorylation sites altered were the casein kinase 2 phosphorylation sites in the regulatory domain and tyrosine 336, a proposed regulatory phosphorylation site. Three mutants involving alanine substitution for basic amino acid residues included one mutant in the PASE domain and two more mutants in the C2 domain. It was observed that GFP-PTEN translocates to the plasma membrane upon EGF stimulation. The mimic of constitutive phosphorylation of the Casein kinase 2 sites resulted in cytoplasmic localization whereas the non-phosphorylated mimic was plasma membrane localized regardless of EGFR activation status. Neutralization of positive charge in the PASE and C2 domains seriously impeded the ability of PTEN to bind to phosphorylated phosphatidylinositol lipids and abolished the ability of the protein to translocate to the plasma membrane in response to receptor activation. Located within a cluster of positively charged lysine residues in the C2 domain is a potential phosphorylation site at tyrosine 336. The phosphorylation mimic showed decreased binding to some membrane lipids compared to the non-phosphorylated mimic.
The results we generated are consistent with a current model for PTEN regulation that proposes PTEN is localized to the cytoplasm in quiescent cells and dephosphorylation of the regulatory domain occurs upon EGF stimulation allowing translocation to the plasma membrane. The model proposes that dephosphorylation of the casein kinase 2 sites unmasks regions of positive charge that interact with the anionic plasma membrane. Furthermore, the results suggested that at the plasma membrane p85 interacts with PTEN to increase lipid phosphatase activity and may be involved in targeting PTEN to the activated receptor where PI3,4,5P3 lipids are being produced.
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Characterizing the Evolutionary Dynamics of Protein Phosphorylation Sites for Functional Phospho-proteomicsTan, Soon Heng 31 August 2012 (has links)
Protein phosphorylation is a prevalent reversible post-translational modification that influences protein functions. The advent of phospho-proteomic technologies now enables proteome-wide quantitative detection of residues phosphorylated under different physiological conditions. The functional consequences of the majority of these phosphorylation events are unknown. This calls for endeavors to characterize their molecular functions and cellular effects. This can be facilitated by systematic approaches to categorize phosphorylation events, interpret their importance and infer their functions. I carried out comparative, evolutionary and integrative analyses on in vivo phosphorylation events to address these challenges. First, I performed cross-species comparative phospho-proteomic analysis to identify evolutionarily conserved phosphorylation events in human. A sequence alignment approach was used to identify phosphorylation events conserved at similar sequence positions across orthologous proteins and a network alignment approach was applied to identify potential evolutionarily conserved kinase-substrate interactions. Conserved human phosphoproteins identified are found enriched for proteins encoded by known cancer- and disease-associated genes. Next, I developed a new approach to analyze the sequence conservation of known phosphorylated residues on human, mouse and yeast proteins that factored in the background mutational rates of protein and phosphorylatable residue. Furthermore, sites were analyzed according to (i) characterized functions, (ii) prevalence, (iii) stoichiometry, their occurrence in (iv) structurally disordered/ordered protein regions, in (v) proteins of various abundance and in (vi) proteins with different protein interaction propensity to identify the factors influencing sequence conservation of phosphorylated residues. Importantly, my analysis suggests that false positives and randomly phosphorylated residues are present in existing phosphorylation datasets and they are more common on high abundance proteins. Lastly, I characterized the theoretical maximum phosphorylation capacity in terms of phosphorylatable residues and discovered that genomic tyrosine frequency correlates negatively and significantly with tyrosine kinase frequency and cell type in metazoan. This observation suggests that fidelity of phosphotyrosine signaling occurred partially through global tyrosine depletion.
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Role of the Adapter Protein 3BP2 in BCR-ABL-mediated Signal Transduction and LeukemogenesisJarvis, Jordan 20 November 2012 (has links)
3BP2 was originally identified through its interaction with the ABL kinase. Fusion of ABL with the BCR gene forms the BCR-ABL onco-protein, which is causative in Chronic Myeloid Leukemia (CML) and acute lymphoid leukemia (ALL). Due to the ability of 3BP2 to regulate ABL activity in osteoblasts, we hypothesize that 3BP2 modulates BCR-ABL signalling. Overexpression of 3BP2 in the CML-T1 cell line produced a marked decrease in global tyrosine phosphorylation. 3BP2 overexpression also resulted in a significant increase in CML-T1 cell growth, accompanied by altered ERK1/2, AKT, SYK, LYN, HCK, and CBL phosphorylation and expression. A phospho-SRC family protein and a 116 kDa phospho-protein were identified as 3BP2 interaction partners in response to BCR-ABL activation. BCR-ABL bone marrow transplantation (BMT) models in 3bp2-/- mice exhibit accelerated disease compared to wild-type mice, with altered leukemic phenotype. In conclusion, 3BP2 is able to modulate signalling through BCR-ABL and affect BCR-ABL-induced disease outcome.
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Characterizing the Evolutionary Dynamics of Protein Phosphorylation Sites for Functional Phospho-proteomicsTan, Soon Heng 31 August 2012 (has links)
Protein phosphorylation is a prevalent reversible post-translational modification that influences protein functions. The advent of phospho-proteomic technologies now enables proteome-wide quantitative detection of residues phosphorylated under different physiological conditions. The functional consequences of the majority of these phosphorylation events are unknown. This calls for endeavors to characterize their molecular functions and cellular effects. This can be facilitated by systematic approaches to categorize phosphorylation events, interpret their importance and infer their functions. I carried out comparative, evolutionary and integrative analyses on in vivo phosphorylation events to address these challenges. First, I performed cross-species comparative phospho-proteomic analysis to identify evolutionarily conserved phosphorylation events in human. A sequence alignment approach was used to identify phosphorylation events conserved at similar sequence positions across orthologous proteins and a network alignment approach was applied to identify potential evolutionarily conserved kinase-substrate interactions. Conserved human phosphoproteins identified are found enriched for proteins encoded by known cancer- and disease-associated genes. Next, I developed a new approach to analyze the sequence conservation of known phosphorylated residues on human, mouse and yeast proteins that factored in the background mutational rates of protein and phosphorylatable residue. Furthermore, sites were analyzed according to (i) characterized functions, (ii) prevalence, (iii) stoichiometry, their occurrence in (iv) structurally disordered/ordered protein regions, in (v) proteins of various abundance and in (vi) proteins with different protein interaction propensity to identify the factors influencing sequence conservation of phosphorylated residues. Importantly, my analysis suggests that false positives and randomly phosphorylated residues are present in existing phosphorylation datasets and they are more common on high abundance proteins. Lastly, I characterized the theoretical maximum phosphorylation capacity in terms of phosphorylatable residues and discovered that genomic tyrosine frequency correlates negatively and significantly with tyrosine kinase frequency and cell type in metazoan. This observation suggests that fidelity of phosphotyrosine signaling occurred partially through global tyrosine depletion.
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Altered regulation of PTEN by mutagenesis and p85 bindingPastor, M Chris 19 August 2008 (has links)
Growth and proliferation are normal functions of cells mediated in part via receptor tyrosine kinases such as the epidermal growth factor (EGF) receptor (EGFR). The EGFR binds the extracellular signaling ligand EGF and transduces the signal into the cell. Phosphatidylinositol 3'-kinase (PI3K) responds to EGFR activation and initiates downstream signaling cascades responsible for cell cycle entry, proliferation and inhibition of apoptosis. Cell cycle arrest is required to stop cell growth and proliferation as well as allow apoptosis, if required. The phosphatase and tensin homologue deleted on chromosome ten (PTEN) directly opposes PI3K signaling since its substrate is the PI3K product phosphatidylinositol 3,4,5-trisphosphate. PI3K is a heterodimer composed of a p85 regulatory subunit and a p110 catalytic subunit. PTEN is an essential tumor suppressor protein. Absence of PTEN has been associated with several types of cancer. <p>Our laboratory has characterized new specialized functions for the p85 protein. One function discovered was the ability of p85 to enhance PTEN lipid phosphatase activity. In this thesis PTEN activity is shown to be enhanced at least 3.5 fold in vitro by an equimolar amount of p85. <p>We performed an analysis of PTEN using seven PTEN mutants. Two types of mutants were created: i) regulatory or possible regulatory phosphorylation sites were substituted to mimic both phosphorylated and non-phosphorylated states and ii) alanine substitution of basic amino acid residues. The phosphorylation sites altered were the casein kinase 2 phosphorylation sites in the regulatory domain and tyrosine 336, a proposed regulatory phosphorylation site. Three mutants involving alanine substitution for basic amino acid residues included one mutant in the PASE domain and two more mutants in the C2 domain. It was observed that GFP-PTEN translocates to the plasma membrane upon EGF stimulation. The mimic of constitutive phosphorylation of the Casein kinase 2 sites resulted in cytoplasmic localization whereas the non-phosphorylated mimic was plasma membrane localized regardless of EGFR activation status. Neutralization of positive charge in the PASE and C2 domains seriously impeded the ability of PTEN to bind to phosphorylated phosphatidylinositol lipids and abolished the ability of the protein to translocate to the plasma membrane in response to receptor activation. Located within a cluster of positively charged lysine residues in the C2 domain is a potential phosphorylation site at tyrosine 336. The phosphorylation mimic showed decreased binding to some membrane lipids compared to the non-phosphorylated mimic.
The results we generated are consistent with a current model for PTEN regulation that proposes PTEN is localized to the cytoplasm in quiescent cells and dephosphorylation of the regulatory domain occurs upon EGF stimulation allowing translocation to the plasma membrane. The model proposes that dephosphorylation of the casein kinase 2 sites unmasks regions of positive charge that interact with the anionic plasma membrane. Furthermore, the results suggested that at the plasma membrane p85 interacts with PTEN to increase lipid phosphatase activity and may be involved in targeting PTEN to the activated receptor where PI3,4,5P3 lipids are being produced.
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The role of interleukin-1 receptor in intestinal damage induced by burn in miceHsu, Wei-hon 31 August 2004 (has links)
Burn induces the inflammation response, and causes the intestinal barrier failure. The failure of intestinal barrier may cause organ damage. Pervious studies have shown that the increase of iNOS activity is closely related to the organ damage after burn. The expression of iNOS is regulated by the activation of NF-£eB, and that is regulated by MAPKs. The pro-inflammatory cytokines play important roles to promote the inflammation through activating a series of signal transduction cascade, via binding to their receptors on cell membrane. The signal transduction cascades are turn on, MAPKs and NF-£eB are activated and the expression of iNOS is promoted. In this study, the role of pro-inflammatory cytokine interleukin-1 receptor (IL-1R) in burn induced intestinal damage was focused on. In experiments, the animals (C57BL/6 mice) were undergone 30~35 % total body surface area (TBSA) burn. The change of intestinal permeability was examined, and intestinal mucosa was assayed for the activation of iNOS and MAPKs by immunoblotting, and the activation of NF-£eB was detected by EMSA. The results reveal that activation of NF-£eB, intestinal permeability and expression of iNOS were increased after burn in wild type mice (WT). ERK MAPK plays an important role to regulate the activation of NF-£eB and expression of iNOS. Surprisingly, the permeability had no change after burn in IL-1R knock out mice (KO). The activation of ERK, NF-£eB and the expression of iNOS were also measured in KO. The levels of p-ERK, NF-£eB activation and iNOS expression were low in KO. When WT mice were treated with U0126 (5 mg/kg i.p.) right after burn to block the activation of ERK, the activation of ERK and NF-£eB, the expression of iNOS, and the intestinal permeability were all decreased significantly. To sum up, the changes in iNOS expression, NF-£eB activation, and intestinal permeability increase are mostly related to the activation of ERK after burn. IL-1 R plays a promotion role in ERK, NF-£eB activation, and iNOS expression that lead to the increase in intestinal permeability and promote damage in intestine.
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Cell Biology of Caveolae and Its Implication for Clinical MedicineFUJIMOTO, TOYOSHI 05 1900 (has links)
No description available.
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Deregulation of signal transduction pathways : by the latent viral oncoproteins of Kaposi's sarcoma herpesvirus (KSHV/HHV-8) /Bubman, Darya. January 2007 (has links)
Thesis (Ph. D.)--Cornell University, January, 2007. / Vita. Includes bibliographical references (leaves 146-195).
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Predicting homologous signaling pathways using machine learningBostan, Babak. January 2009 (has links)
Thesis (M. Sc.)--University of Alberta, 2009. / Title from PDF file main screen (viewed on Nov. 27, 2009). "A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science, Department of Computing Science, University of Alberta." Includes bibliographical references.
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