Academic literature on the topic 'Arg tyrosine kinase'
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Journal articles on the topic "Arg tyrosine kinase"
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Tanis, Keith Q., Darren Veach, Henry S. Duewel, William G. Bornmann, and Anthony J. Koleske. "Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation." Molecular and Cellular Biology 23, no. 11 (June 1, 2003): 3884–96. http://dx.doi.org/10.1128/mcb.23.11.3884-3896.2003.
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ABSTRACT The activities of the related Abl and Arg nonreceptor tyrosine kinases are kept under tight control in cells, but exposure to several different stimuli results in a two- to fivefold stimulation of kinase activity. Following the breakdown of inhibitory intramolecular interactions, Abl activation requires phosphorylation on several tyrosine residues, including a tyrosine in its activation loop. These activating phosphorylations have been proposed to occur either through autophosphorylation by Abl in trans or through phosphorylation of Abl by the Src nonreceptor tyrosine kinase. We show here that these two pathways mediate phosphorylation at distinct sites in Abl and Arg and have additive effects on Abl and Arg kinase activation. Abl and Arg autophosphorylate at several sites outside the activation loop, leading to 5.2- and 6.2-fold increases in kinase activity, respectively. We also find that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity. The autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Src family kinases from cell surface receptors.
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Okuda, Keiko, Ellen Weisberg, D. Gary Gilliland, and James D. Griffin. "ARG tyrosine kinase activity is inhibited by STI571." Blood 97, no. 8 (April 15, 2001): 2440–48. http://dx.doi.org/10.1182/blood.v97.8.2440.
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Abstract The tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces hematologic remission in most patients with chronic myeloid leukemia. In addition to BCR/ABL, STI571 also inhibits v-Abl, TEL/ABL, the native platelet-derived growth factor (PDGF)β receptor, and c-KIT, but it does not inhibit SRC family kinases, c-FMS, FLT3, the epidermal growth factor receptor, or multiple other tyrosine kinases. ARG is a widely expressed tyrosine kinase that shares substantial sequence identity with c-ABL in the kinase domain and cooperates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of leukemia as a fusion partner of TEL. A TEL/ARG fusion was constructed to determine whether ARG can be inhibited by STI571. When expressed in the factor-dependent murine hematopoietic cell line Ba/F3, the TEL/ARG protein was heavily phosphorylated on tyrosine, increased tyrosine phosphorylation of multiple cellular proteins, and induced factor-independent proliferation. The effects of STI571 on Ba/F3 cells transformed with BCR/ABL, TEL/ABL, TEL/PDGFβR, or TEL/ARG were then compared. STI571 inhibited tyrosine phosphorylation and cell growth of Ba/F3 cells expressing BCR/ABL, TEL/ABL, TEL/PDGFβR, and TEL/ARG with an IC50 of approximately 0.5 μM in each case, but it had no effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 cells transformed by TEL/JAK2. Culture of TEL/ARG-transfected Ba/F3 cells with IL-3 completely prevented STI571-induced apoptosis in these cells, similar to what has been observed with BCR/ABL- or TEL/ABL-transformed cells. These results indicate that ARG is a target of the small molecule, tyrosine kinase inhibitor STI571.
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Ha, Byung Hak, Mark Adam Simpson, Anthony J. Koleske, and Titus J. Boggon. "Structure of the ABL2/ARG kinase in complex with dasatinib." Acta Crystallographica Section F Structural Biology Communications 71, no. 4 (March 20, 2015): 443–48. http://dx.doi.org/10.1107/s2053230x15004793.
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ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases. ARG plays important roles in cell morphogenesis, motility, growth and survival, and many of these biological roles overlap with the cellular functions of the ABL kinase. Chronic myeloid leukemia (CML) is associated with constitutive ABL kinase activation resulting from fusion between parts of the breakpoint cluster region (BCR) andABL1genes. Similarly, fusion of theETV6(Tel) andARGgenes drives some forms of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Dasatinib is a tyrosine kinase inhibitor used for the treatment of CML by inhibiting ABL, and while it also inhibits ARG, there is currently no structure of ARG in complex with dasatinib. Here, the co-crystal structure of the mouse ARG catalytic domain with dasatinib at 2.5 Å resolution is reported. Dasatinib-bound ARG is found in the DFG-in conformation although it is nonphosphorylated on the activation-loop tyrosine. In this structure the glycine-rich P-loop is found in a relatively open conformation compared with other known ABL family–inhibitor complex structures.
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Plattner, Rina, Anthony J. Koleske, Andrius Kazlauskas, and Ann Marie Pendergast. "Bidirectional Signaling Links the Abelson Kinases to the Platelet-Derived Growth Factor Receptor." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2573–83. http://dx.doi.org/10.1128/mcb.24.6.2573-2583.2004.
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ABSTRACT The c-Abl nonreceptor tyrosine kinase is activated by growth factor signals such as the platelet-derived growth factor (PDGF) and functions downstream of the PDGF-β receptor (PDGFR) to mediate biological processes such as membrane ruffling, mitogenesis, and chemotaxis. Here, we show that the related kinase Arg is activated downstream of PDGFRs in a manner dependent on Src family kinases and phospholipase C γ1 (PLC-γ1)-mediated phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, as we showed previously for c-Abl. PIP2, a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits the tyrosine kinase activities of both Arg and c-Abl in vitro and in cells. We now demonstrate that c-Abl and Arg form inducible complexes with and are phosphorylated by the PDGFR tyrosine kinase in vitro and in vivo. Moreover, c-Abl and Arg, in turn, phosphorylate the PDGFR. We show that c-Abl and Arg exhibit nonredundant functions downstream of the activated PDGFR. Reintroduction of c-Abl into Arg-Abl double-null fibroblasts rescues the ability of PLC-γ1 to increase PDGF-mediated chemotaxis, while reexpression of Arg fails to rescue the chemotaxis defect. These data show that, although both kinases are activated and form complexes with proteins in the PDGFR signaling pathway, only c-Abl functions downstream of PLC-γ1 to mediate chemotaxis.
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Moresco, Eva Marie Yang, Alfred J. Scheetz, William G. Bornmann, Anthony J. Koleske, and Reiko Maki Fitzsimonds. "Abl Family Nonreceptor Tyrosine Kinases Modulate Short-Term Synaptic Plasticity." Journal of Neurophysiology 89, no. 3 (March 1, 2003): 1678–87. http://dx.doi.org/10.1152/jn.00892.2002.
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Abl family nonreceptor tyrosine kinases regulate cell morphogenesis through functional interactions with the actin cytoskeleton. The vertebrate Abl family kinases, Abl and Arg, are expressed in the adult mouse brain, where they may regulate actin cytoskeletal dynamics in mature neurons. Using immunoelectron microscopy, we have localized Abl and Arg to the pre- and postsynaptic compartments of synapses in the mouse hippocampal area CA1. Paired-pulse facilitation (PPF) was significantly reduced at the Schaffer collateral-CA1 (SC-CA1) excitatory synapses in hippocampal slices from abl−/− and arg−/− mice as compared with wild-type mice. Furthermore, treatment of wild-type slices with the specific Abl family kinase inhibitor STI571 also reduced PPF. Basal synaptic transmission, posttetanic potentiation (PTP), long-term potentiation (LTP), and long-term depression (LTD) were similar to wild-type controls in abl−/− and arg−/− slices and in STI571-treated wild-type slices. These results indicate that an important function of Abl and Arg is to modulate synaptic efficacy via a presynaptic mechanism during repetitive activation.
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Peacock, Justin G., Ann L. Miller, William D. Bradley, Olga C. Rodriguez, Donna J. Webb, and Anthony J. Koleske. "The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin." Molecular Biology of the Cell 18, no. 10 (October 2007): 3860–72. http://dx.doi.org/10.1091/mbc.e07-01-0075.
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In migrating cells, actin polymerization promotes protrusion of the leading edge, whereas actomyosin contractility powers net cell body translocation. Although they promote F-actin–dependent protrusions of the cell periphery upon adhesion to fibronectin (FN), Abl family kinases inhibit cell migration on FN. We provide evidence here that the Abl-related gene (Arg/Abl2) kinase inhibits fibroblast migration by attenuating actomyosin contractility and regulating focal adhesion dynamics. arg−/− fibroblasts migrate at faster average speeds than wild-type (wt) cells, whereas Arg re-expression in these cells slows migration. Surprisingly, the faster migrating arg−/− fibroblasts have more prominent F-actin stress fibers and focal adhesions and exhibit increased actomyosin contractility relative to wt cells. Interestingly, Arg requires distinct functional domains to inhibit focal adhesions and actomyosin contractility. The kinase domain–containing Arg N-terminal half can act through the RhoA inhibitor p190RhoGAP to attenuate stress fiber formation and cell contractility. However, Arg requires both its kinase activity and its cytoskeleton-binding C-terminal half to fully inhibit focal adhesions. Although focal adhesions do not turn over efficiently in the trailing edge of arg−/− cells, the increased contractility of arg−/− cells tears the adhesions from the substrate, allowing for the faster migration observed in these cells. Together, our data strongly suggest that Arg inhibits cell migration by restricting actomyosin contractility and regulating its coupling to the substrate through focal adhesions.
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Yokota, Asumi, Hideyo Hirai, Tsukimi Shoji, Taira Maekawa, and Keiko Okuda. "C-Terminal Domain of ABL Family Kinases, ABL and ARG, Defines Their Distinct Leukemogenic Activities in Vivo." Blood 124, no. 21 (December 6, 2014): 2368. http://dx.doi.org/10.1182/blood.v124.21.2368.2368.
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Abstract ARG (ABL2) is a member of ABL family kinases and highly homologous to ABL (ABL1) except the C-terminal domain adjacent to the kinase domain. TEL/ARG that consists of ARG fused to TEL (ETV6) has been found in AML M3, M4 or T-ALL patients, with additional chromosomal abnormalities of t(15;17)(q12;q21), inv(16)(p13;q12) or t(1;10;12)(q25;q23;p13) translocation, respectively. The structure of TEL/ARG is similar to that of TEL/ABL, which has been found in patients with T-ALL, B-ALL, AML and CML. TEL mediates homo-oligomerization of these fusion proteins, TEL/ABL and TEL/ARG, resulting in constitutive activation of the tyrosine kinases. Although ABL fusion proteins such as BCR/ABL and TEL/ABL have been intensively investigated, the involvement of TEL/ARG in leukemogenesis is not fully elucidated yet. We have recently reported that in vitro transforming activity of TEL/ARG was significantly lower than that of TEL/ABL although their kinase activities were almost identical. Interestingly, the in vitro transforming activities of C-terminus-swapped mutants, TEL/ABL with C-terminal domain of ARG [TEL-ABL (ARG-C)] or TEL/ARG with C-terminal domain of ABL [TEL/ARG (ABL-C)], were comparable to those of TEL/ARG or TEL/ABL, respectively, while kinase activities in the swapped mutants were not altered. These results suggest that C-termini of ABL family kinases contain some functional domain that defines their distinct transforming activities. The purpose of this study is to compare the in vivo leukemogenic activities of TEL/ABL and TEL/ARG, and evaluate the impact of the C-terminal domains. First, we investigated whether TEL/ABL or TEL/ARG caused leukemia in mice. Each fusion gene together with GFP gene was retrovirally transduced into the bone marrow cells harvested from C57BL/6 mice treated with 5-fluorouracil, and the transduced cells were transplanted into lethally irradiated mice. Similar to BCR/ABL, transplantation of TEL/ABL-transduced cells induced rapid myeloproliferative status accompanied by hepatomegaly and/or splenomegaly, and all the recipient mice died within 33 days after transplantation, indicating the development of myeloid leukemia. In contrast, the recipient mice transplanted with TEL/ARG-transduced cells did not develop myeloid leukemia but infiltrative mastocytosis, and died around 200 days after transplantation (Figure 1). Hemophagocytic mast cells accumulating in the bone marrow, and mast cells circulating in the peripheral blood were also observed in these mice. Next we investigated the roles of C-terminal domains of ABL and ARG in their in vivo leukemogenic activities. C-terminus-swapped mutants, TEL/ABL (ARG-C) and TEL/ARG (ABL-C) were retrovirally transduced into bone marrow cells and the transduced cells were transplanted as described above. Intriguingly, TEL/ABL (ARG-C) mutant failed to cause myeloproliferative status or leukemia at day 153 (Figure 2A). On the other hand, TEL/ARG (ABL-C) induced lethal myeloid leukemia in 4 out of 13 mice (30.8%) within 111 days after transplantation (Figure 2B). Collectively, the in vivo phenotypes induced by TEL/ABL (ARG-C) or TEL/ARG (ABL-C) resembled those induced by TEL/ARG or TEL/ABL, respectively. Mastocytosis, a characteristic of TEL-ARG-induced phenotype, has not been observed so far in any of the recipients of TEL/ABL (ARG-C) or TEL/ARG (ABL-C). In conclusion, these results indicate that C-terminal domain of ABL family kinases defines their distinct leukemogenic activities in vivo through modulating both proliferation and differentiation. Notably, C-terminus of ARG strongly suppressed the in vivo leukemogenic activity of TEL/ABL without impairing the tyrosine kinase activity. Further clarification of the molecular mechanisms underlying the suppressive activity of C-terminus of ARG will lead to development of a novel therapeutic strategy, especially for patients with CML harboring mutations, which are resistant to tyrosine kinase inhibitors. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
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Okuda, Keiko, Nari Harakawa, Richard A. VanEtten, Nihal Patel, Naochika Domae, Yuko Sato, and Hideyo Hirai. "Distinct Transforming and Leukemogenic Activities of Tel-Arg and Tel-Abl Oncogenes in Mice: Possible Negative Role for the Transforming Activity in C-Terminus of Arg." Blood 112, no. 11 (November 16, 2008): 2845. http://dx.doi.org/10.1182/blood.v112.11.2845.2845.
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Abstract ARG (ABL2) is a member of ABL tyrosine kinase gene family that is highly homologous to c-ABL (ABL1) in overall domain structure (SH3-SH2-SH1) and amino acid sequence. ARG has recently been implicated in the pathogenesis of human acute leukemia though t(1;12) translocations that fuse a transcription factor gene, ETV6/TEL, to ARG (Iijima et al., Blood2000;95:2126). The resulting TEL-ARG fusion tyrosine kinase is similar in structure to the TEL-ABL fusion found in some acute leukemia and atypical CML patients, and, like TEL-ABL, can transform Ba/F3 cells and fibroblasts in vitro and activate a similar set of intracellular signaling pathways (Iijima et al., Oncogene2002;21:4374). To assess the leukemogenic activity of TEL-ARG, we co-expressed TEL-ARG with GFP in mouse bone marrow using a retroviral bone marrow transduction/transplantation strategy. Whereas TEL-ABL induces rapidly fatal myelolproliferative disease (MPD) in recipient mice (Million et al., Blood2000;96:664), recipients of TEL-ARG-transduced BM did not develop overt MPD, but succumbed instead to long-latency (30–45 weeks) T-cell acute lymphoblastic leukemia/lymphoma characterized by modest leukocytosis and a malignant pleural effusion composed of Thy-1+B220- tumor cells. To study the molecular basis of the marked difference in the leukemogenic activity of TEL-ARG and TEL-ABL, we produced TEL-ARG mutants that swapped the kinase domain or C-terminus of ARG with the corresponding domain in ABL. The mutants were introduced into Ba/F3 cells by retroviral transduction and transduced cells selected for equal expression of the fusion protein by flow sorting for populations with equivalent intensity of GFP fluorescence. All chimeric proteins were expressed and showed equivalent levels of auto-phosphorylation by western blot analysis of the sorted cells. However, the quantitative transforming activity of TEL-ARG in Ba/F3 cells, measured by the number of days required to achieve measurable cell growth following IL-3 deprivation, was significantly lower than for TEL-ABL (25 ± 4.3 days for TEL-ARG vs. 1 to 2 days for TEL-ABL). A TEL-ARG mutant containing the ABL kinase domain was similar to TEL-ARG in this assay, but replacing the ARG C-terminal domain with that of ABL increased Ba/F3 transformation to levels equivalent to TEL-ABL. To further dissect the functional domains that are responsible for this effect, a new series of mutants containing internal deletions in ARG C-terminus of TEL-ARG [aa.826–976 (Delta Box1), aa.977–1213 (Delta Box2), aa 1214–1316 (Delta Box3), aa.1317–1465 (Delta Box4)] were generated. Regarding to their function, only Box2 and Box4 were reported as F- or F,G- actin binding domain. From a preliminary study using the cell lines which express each of the mutants, Delta Box 1 clones obtained an accelerated proliferation which compared with that of Tel-Abl, suggesting that there is a disadvantage for cell proliferation by ARG c-terminus. These results indicate that distinct bio-phenotype associated with Abl family tyrosine kinase is the most likely regulated by their c-terminus and the c-terminus of Arg contains functional subdomain that impairs growth signal induced by Abl family tyrosine kinase.
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Cao, Cheng, Xinping Ren, Surender Kharbanda, Anthony Koleske, K. V. S. Prasad, and Donald Kufe. "The ARG Tyrosine Kinase Interacts with Siva-1 in the Apoptotic Response to Oxidative Stress." Journal of Biological Chemistry 276, no. 15 (February 23, 2001): 11465–68. http://dx.doi.org/10.1074/jbc.c100050200.
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The Abl family of mammalian nonreceptor tyrosine kinases consists of c-Abl and ARG (Abl-related gene). Certain insights are available regarding the involvement c-Abl in the response of cells to stress. ARG, however, has no known function in cell signaling. The present studies demonstrate that ARG associates with the proapoptotic Siva-1 protein. The functional significance of the ARG-Siva-1 interaction is supported by the finding that ARG is activated by oxidative stress and that this response involves ARG-mediated phosphorylation of Siva-1 on Tyr48. The proapoptotic effects of Siva-1 are accentuated in cells stably expressing ARG and are inhibited in ARG-deficient cells. Moreover, the proapoptotic effects of Siva-1 are abrogated by mutation of the Tyr48site. We also show that the apoptotic response to oxidative stress is attenuated in ARG-deficient cells and that this defect is corrected by reconstituting ARG expression. These findings support a model in which the activation of ARG by oxidative stress induces apoptosis by a Siva-1-dependent mechanism.
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Swimm, Alyson, Bettina Bommarius, Yue Li, David Cheng, Patrick Reeves, Melanie Sherman, Darren Veach, William Bornmann, and Daniel Kalman. "EnteropathogenicEscherichia coliUse Redundant Tyrosine Kinases to Form Actin Pedestals." Molecular Biology of the Cell 15, no. 8 (August 2004): 3520–29. http://dx.doi.org/10.1091/mbc.e04-02-0093.
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Enteropathogenic Escherichia coli (EPEC) are deadly contaminants in water and food and induce protrusion of actin-rich membrane pedestals beneath themselves upon attachment to intestinal epithelia. EPEC then causes intestinal inflammation, diarrhea, and, among children, death. Here, we show that EPEC uses multiple tyrosine kinases for formation of pedestals, each of which is sufficient but not necessary. In particular, we show that Abl and Arg, members of the Abl family of tyrosine kinases, localize and are activated in pedestals. We also show that pyrido[2,3-d]pyrimidine (PD) compounds, which inhibit Abl, Arg, and related kinases, block pedestal formation. Finally, we show that Abl and Arg are sufficient for pedestal formation in the absence of other tyrosine kinase activity, but they are not necessary. Our results suggest that additional kinases that are sensitive to inhibition by PD also can suffice. Together, these results suggest that EPEC has evolved a mechanism to use any of several functionally redundant tyrosine kinases during pathogenesis, perhaps facilitating its capacity to infect different cell types. Moreover, PD compounds are being developed to treat cancers caused by dysregulated Abl. Our results raise the possibility that PD may be useful in treating EPEC infections, and because PD affects host and not bacterium, selecting resistant strains may be far less likely than with conventional antibiotics.
Dissertations / Theses on the topic "Arg tyrosine kinase"
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ANGELONI, VALENTINA. "Studio e caratterizzazione delle isoforme della tirosino chinasi non recettoriale ARG nel differenziamento neuronale in vitro." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/7823.
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Il gene umano ARG (o ABL2) codifica per una proteina che appartiene alla sottofamiglia Abelson delle tirosino chinasi non recettoriali (Kruh et al.,1990; Perego et al., 1991). Arg in vitrù dei domini di legame alle proteine del citoscheltro (Hernandez et al., 2004a e Miller et al., 2004) e al coinvolgimento, mediante la sua attività chinasica, nei pathway molecolari di riarrangiamento del citoscheletro (Galkin et al., 2005) è attivamente coinvolto nel processo di neuritogenesi e di formazione e funzione delle sinapsi (Koleske et al., 1998). Come per c-Abl anche per Arg sono state descritte, per splicing alternativo dell’esone 1, due isoforme N-terminali (1A e 1B) (Kruh et al., 1990). Nel nostro laboratorio sono state identificate con metodiche di RT-PCR qualitativa nuovi trascritti di Arg che predicono isoforme con diverse estremità 5' e 3' (Perego et al., 2005). Per quanto riguarda le estremità 5' si è dimostrato che l’escissione alternativa dell’esone 2, giustapposto all’esone 1A o 1B, produce quattro diversi trascritti definiti B-Long (BL), B-Short (BS), A-Long (AL) e A-Short (AS) (Perego et al., 2005). Le forme "Long" mantengono l’esone 2 costituito da 63 paia di basi e lo splicing alternativo di questo esone non interrompe l’open reading frame della proteina. All’estremità 3' sono state invece identificate 2 ulteriori isoforme che differiscono per una sequenza, detta ΔCT, di 309 paia di basi corrispondenti a 103 amminoacidi e che sono state definite come "Short" e "Long" (CTS e CTL) a seconda che abbiano perso o meno questa sequenza; la delezione della sequenza ΔCT elimina parte del primo sito legante l’actina (Perego et al., 2005). I trascritti corrispondenti alle diverse estremità 5' e 3' sono differentemente espressi nei vari tipi cellulari e durante la differenziazione mieloide e linfoide (Perego et al., 2005). Combinando i diversi splicing dell’estremità 5' e 3' è possibilie ipotizzare l’esistenza di otto diverse isoforme full-length di Arg (ASCTS, ALCTS, ASCTL, ALCTL, BSCTS, BLCTS, BSCTL e BLCTL), dotate di diversa possibilità di interazione con il citoscheletro e differente coinvolgimento in pathways metabolici.
Per dimostrare l’effettiva espressione endogena dei trascritti corrispondenti alle otto diverse isoforrme full-ength di Arg abbiamo prima analizzato, mediante Real-Time PCR, il pattern d’espressione delle diverse estremità 5' e 3' del trascritto di Arg nelle linee cellulari renali Hek 293T e Caki-1. Abbiamo così evidenziato che le estremità 5' sono tutte espresse solo nelle cellule Caki-1, a differenza delle cellule Hek 293T, che esprimono solo le forme B. Le estremità 3' invece sono espresse, anche se con rapporti quantitativi differenti, in entrambe le linee.
La linea cellulare Caki-1 è stata quindi utilizzata per dimostrare l’effettiva espressione dei trascritti corrispondenti alle 8 diverse isoforme di Arg mediante cicli sequenziali di PCR (Long e Nested PCR) che utilizzavano combinazioni di diversi primers specifici. La presenza di amplificati della dimensione attesa per le diverse isoforme full-length dimostra, in queste linea cellulare, l’effettiva espressione di tutti 8 i trascritti full-length di Arg predetti.
Una volta dimostrata l’esistenza delle otto isoforme di Arg abbiamo cercato di valutarne il coinvolgimento in un modello di differenziamento neuronale "in vitro", basandoci sui dati di letteratura che vedono Arg coinvolto nella neuritogenesi e nella formazione e funzione delle sinapsi (Koleske et al., 1998). Pertanto la linea cellulare di neuroblastoma umano SH-SY5Y è stata indotta al differenziamento per trattamento con ATRA (All-Trans-Retinoic-Acid) e Abeta (peptide amiloidogeno (Aβ1-42)), che come documentato in letteratura è dotata a basse concentrazioni di attività neurotrofica (Susen and Blochl, 2005). L’effetto differenziativo prodotto sulla linea cellulare SH-SY5Y da questi trattamenti è stato documentato mediante analisi morfologica e in immunofluorescenza, mentre tramite Real-Time PCR e western blot si sono quantificati i livelli del trascritto e della proteina di Arg prima e dopo trattamento ed analizzati i livelli di espressione relativa dei trascritti corrispondenti alle diverse estremità 5' e 3', allo scopo di evidenziare eventuali variazioni in corso di differenziamento. Inoltre sulla base dei dati di letteratura che evidenziano il ruolo di Arg come promotore della neuritogenesi in cellule di neuroblastoma N2A (Hernandez et al., 2004b) per attivazione dell’inibitore di Rho p190RhoGAP, in seguito a fosforilazione Arg-dipendente della sua tirosina 1105 (Y1105), è stato analizzato il livello di p190RhoGAP fosforilato in Y1105. Nelle cellule SH-SY5Y, trattate con 20μM ATRA per 6 giorni, Arg sembra essere coinvolto in un pathway neurodifferenziativo p190RhoGAP-dipendente, infatti il trascritto totale di Arg incrementa e sebbene il livello proteico di Arg sia paragonabile a quello delle cellule controllo, il livello di p190RhoGAP fosforilato in Y1105 risulta aumentato. Arg sembra essere coinvolto anche nel processo neurodifferenziativo a cui le cellule SH-SY5Y vanno incontro per trattamento con 0,01μM Abeta per 72 ore, infatti l’analisi mediante Real-Time PCR e western blot ha mostrato un’over-espressione sia del trascritto che della proteina totale di Arg nelle cellule SH-SY5Y trattate con Abeta rispetto alle cellule controllo. Inoltre il pattern di espressione delle isoforme di Arg, analizzato tramite Real-Time PCR, ha mostrato una maggiore espressione del trascritto con estremità 3' di tipo CTL rispetto alla controparte CTS, al contrario di quanto succede nelle cellule controllo. L’analisi del livello di p190RhoGAP fosforilato in tirosina 1105 non mostra però nelle cellule trattate con Abeta una variazione rispetto alle cellule controllo. Questi dati fanno ipotizzare un coinvolgimento di Arg in un pathway di neuritogenesi p190RhoGAP-indipendente, diverso quindi da quello attivato dal trattamento con ATRA nelle cellule SH-SY5Y. Del resto è stato anche descritto che in cellule di neuroblastoma N2A la transfezione di Arg può indurre la neuritogenesi senza indurre inibizione di Rho e quindi attraverso un pathway p190RhoGAP-indipendente (Hernandez et al., 2004b). Ulteriori studi sono in corso per valutare il coinvolgimento di Arg in pathway alternativi a quello di Rho nel processo di neuritogenesi indotto da Abeta.
Date le sopra citate caratteristiche di Arg e il suo ruolo nel sistema nervoso centrale visto il ruolo di Abl nel taglio proteolitico del precursore della proteina amiloide (APP) (Perkinton et al., 2004) Abbiamo valutato l’espressione di Arg e delle sue isoforme anche in colture primarie di fibroblasti prelevati da pazienti affetti da Alzheimer rispetto ai controlli sani, riscontrando un’over-espressione del trascritto totale di Arg. Questo dato rappresenta il punto di partenza per studi fututri che mirino a definire il possibile coinvolgimento di Arg nel metabolismo della proteina precursore dall’amiloide APP. Ulteriori studi verranno eseguiti utilizzando concentrazioni potenzialmente neurotossiche di Abeta (2,5μM) per stimolare le cellule SH-SY5Y al fine di valutarne l’effetto sull’espressione delle isoforme di Arg e sulla morfologia cellulare.
Per valutare se le otto diverse isoforme full-length di Arg possono avere ruoli diversi nel differenziamento neuronale abbiamo anche approntato studi di tipo funzionale. Transfettando nella linea cellulare SH-SY5Y le otto diverse isoforme di Arg clonate nel vettore di espressione pFlagCMV2. Questi esperimenti hanno evidenziato che le isoforme BLCTL e BSCTL inducono nelle cellule transfettate l’acquisizione di una morfologia più rotondeggiante e una significativa diminuzione dello "spreading cellulare" rispetto alle cellule transfettate con il vettore controllo (LAC Z). L’isoforma BLCTS è invece tra le isoforme B quella che induce una maggiore produzione di protrusioni cellulari quando transfettate nella linea SH-SY5Y. In seguito a transfezione con le isoforme A, normalmente non espresse in questo tipo cellulare, ed in particolare con l’isoforma ALCTS, le cellule sviluppano un fenotipo ricco di estroflessioni di diversa lunghezza e spesso filopodiformi. Dato il ruolo di Arg, documentato in letteratura, nel riarrangiamento del citoscheletro (Galkin et al., 2005), abbiamo voluto poi valutare l’effetto sul citoscheletro di actina e tubulina dell’over-espressione delle isoforme BLCTS e ALCTS, che quando over-espresse inducono in modo più evidente la formazione di estroflessioni cellulari. Dall’analisi in immunofluorescenza delle cellule transfettate con le due isoforme BLCTS e ALCTS è emerso che quando nelle cellule SH-SY5Y viene over-espressa l’isoforma BLCTS la distribuzione dell’F-actina e della tubulina è corticale e paragonabile a quella delle cellule non transfettate mentre nelle cellule che over-esprimono l’isoforma ALCTS l’F-actina ha ancora una distribuzione corticale e paragonabile a quella delle cellule non transfettate, mentre la tubulina si accumula nel citoplasma dove colocalizza con Arg, diffondendo anche nel nucleo. Verranno eseguiti ulteriori studi per approfondire l’effetto dell’over-espressione delle singole isoforme, sia tramite trasfezioni stabili che inducibili delle otto isoforme full-length di Arg.
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DE, MARCO SOFIA. "STUDY OF THE INTERACTIONS AMONG ARG/ABL2, TGF-β1 AND LOX IN CLEAR CELL RENAL CELL CARCINOMA PROGRESSION." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2020. http://hdl.handle.net/10281/263399.
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In circa il 25-30% dei pazienti con carcinoma renale a cellule chiare (ccRCC) la diagnosi viene fatta quando la malattia è già ad uno stadio avanzato e circa il 30% di questi pazienti presenta metastasi ossee. È stato descritto un coinvolgimento del TGF-β1 nel promuovere aggressività, invasione e metastasi ossee nel ccRCC. Noi abbiamo già dimostrato che l'enzima della matrice extracellulare lisil ossidasi (Lox), noto per promuovere la migrazione e l'invasione cellulare attraverso il riarrangiamento del citoscheletro, è overespresso nel ccRCC. Lox, attraverso l'attivazione degli osteoclasti e l'inibizione degli osteoblasti, ha un ruolo chiave nella formazione delle lesioni ossee premetastatiche nel carcinoma mammario e del colon. Noi abbiamo precedentemente evidenziato che la produzione di TGF-β1 è modulata dalla tirosina chinasi Arg nelle cellule tubulari renali umane. Arg modula, attraverso il riarrangiamento del citoscheletro, l'invasione e la metastatizzazione del carcinoma mammario e prostatico. In base a questi dati e utilizzando come modelli in vitro colture cellulari primarie e linee cellulari, abbiamo valutato le interazioni molecolari tra TGF-β1, Lox e Arg in cellule di ccRCC e gli effetti funzionali di queste interazioni sull'invasione tumorale e sul comportamento degli osteoclasti e degli osteoblasti responsabili della formazione di lesioni ossee premetastatiche. L'espressione e la secrezione di TGF-β1 e Lox, e l'espressione della proteina Arg erano aumentate nelle colture primarie di ccRCC rispetto a quelle di cortex normale. Nelle colture di ccRCC la secrezione di TGF-β1 e Lox era positivamente correlata. Il trattamento con TGF-β1 della linea cellulare di ccRCC, 786-O, aumentava l'espressione e la secrezione di Lox e riduceva il livello della proteina Arg. L'inibitore del recettore del TGF-β SB431542 contrastava questi effetti. L'inibizione del signaling Smad-dipendente del TGF-β con SIS3 e dell'attività del proteasoma con MG132 riaumentava il livello della proteina Arg. Il silenziamento di Arg con un siRNA specifico induceva nelle cellule 786-O un aumento della secrezione di TGF-β1 e Lox, contrastata dal trattamento con SB431542. Inoltre, il silenziamento di Arg nelle cellule 786-O ha ridotto l'invasione cellulare valutata con saggio di invasione 3D in collagene, anche in presenza del trattamento con TGF-β1. L'inibizione del signaling di TGF-β1 con SB431542 riduceva l'invasione cellulare anche in cellule silenziate per Arg. Il trattamento con terreni condizionati di cellule 786-O inibiva la proliferazione degli osteoblasti MC3T3-E1 e aumentava la differenziazione osteoclastica delle cellule RAW264.7, come valutato dalla colorazione della fosfatasi acida resistente al tartrato (TRAP). L'inibitore di Lox, βAPN, contrastava parzialmente questi effetti. I risultati preliminari ottenuti utilizzando i terreni condizionati di colture primarie di ccRCC hanno confermato queste osservazioni. Nel complesso questi dati suggeriscono che nelle cellule di ccRCC Arg modula la produzione di Lox mediante secrezione di TGF-β1 che, a sua volta, modula la stabilità della proteina Arg attraverso un pathway Smad-dipendente. La caratterizzazione delle complesse interazioni tra TGF-β1, Lox e Arg che modulano l'invasione delle cellule di ccRCC e il comportamento degli osteoblasti e degli osteoclasti coinvolti nella formazione di lesioni ossee premetastatiche, può far luce sui meccanismi molecolari della progressione del ccRCC.About 25-30% of clear cell Renal Cell Carcinoma (ccRCC) patients show an advanced stage of disease at the time of diagnosis, and about 30% of these patients have matastasis affecting bones. An involvement of TGF-β1 in promoting ccRCC aggressiveness, invasion and bone metastasis has been described. We previously showed that the extracellular matrix modifying enzyme lysyl oxidase (Lox), which promotes cell migration and invasion through cytoskeleton rearrangement, was overexpressed in ccRCC. Lox has a key role in formation of premetastatic bone lesions in breast and colon cancer through osteoclast activation and osteoblast inhibition. Previous data evidenced that TGF-β1 production is modulated by Arg tyrosine kinase in human renal tubular cells. Arg modulates, through cytoskeleton rearrangement, invasion and metastasis of breast and prostate cancers. Based on these data and using in vitro models of primary cell cultures and cell lines, we evaluated the molecular interactions among TGF-β1, Lox and Arg in ccRCC cells and the functional effects of these interactions on tumor invasion and osteoclast and osteoblast behavior responsible for premetastatic bone lesion formation. The expression and secretion of TGF-β1 and Lox, and Arg protein expression, were increased in ccRCC versus normal cortex primary cultures. In ccRCC cultures TGF-β1 and Lox secretion were positively correlated. TGF-β1 treatment of ccRCC 786-O cell line upregulated Lox expression and secretion and downregulated Arg protein level. The TGFβ-receptor inhibitor SB431542 reverted these effects. Inhibition of Smad-dependent TGF-β pathway by SIS3 and proteasome activity by MG132 rescued Arg protein level. Arg silencing by siRNA in 786-O cells induced an increment of TGF-β1 and Lox secretion, reverted by SB431542 treatment. Moreover, Arg silencing in 786-O cells decreased cell invasion analyzed by 3D invasion assay in collagen, even in presence of TGF-β1 treatment. TGF-β1 signalling inhibition with SB431542 reduced cell invasion even in Arg silenced cells. Treatment with 786-O conditioned media inhibited MC3T3-E1 osteoblast proliferation and increased osteoclastic differentiation of RAW264.7 cells, as evaluated by TRAP staining. Lox inhibitor βAPN partially reverted these effects. Preliminary results obtained using conditioned media of ccRCC primary cultures confirmed these observations. Overall, these data suggest that in ccRCC cells Arg modulates Lox production by secretion of TGF-β1 that, in turn, modulates Arg protein stability through a Smad-dependent pathway. The characterization of the complex interactions among TGF-β1, Lox and Arg, which modulate ccRCC cell invasion and osteoblast and osteoclast behavior involved in premetastatic bone lesion formation, can shed light on the molecular mechanisms of ccRCC progression.
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Bergalet, Julie. "Un nouveau rôle de la tyrosine kinase oncogénique NPM-ALK dans le contrôle de l'expression génique au niveau post-trancriptionnel." Toulouse 3, 2011. http://thesesups.ups-tlse.fr/1506/.
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La protéine hybride à activité tyrosine kinase, NPM-ALK est exprimée dans 75% des Lymphomes Anaplasiques à Grandes Cellules (LAGC). Bien que le phénotype tumoral de ces lymphomes soit en partie associé à l'activation constitutive de nombreuses voies de signalisation (MAPK, PI3K/AKT, Jak/STAT et PLC-gamma), l'identification de nouveaux partenaires de NPM-ALK a permis d'envisager l'existence de nouveaux mécanismes moléculaires participants à son pouvoir oncogénique. Ainsi, la découverte d'interactions entre NPM-ALK et des protéines de liaisons aux ARNm (RNA-Binding protein, RBPs), nous a poussé à émettre l'hypothèse, qu'outre son effet sur la transcription, la tyrosine kinase oncogénique NPM-ALK pouvait également moduler l'expression génique au niveau post-transcriptionnel. Dans la première partie de mon travail (article n°1), j'ai montré que HuR, une AUBP (AU-binding protein qui contrôle le devenir d'ARNm dont l'extrémité 3' non traduite présente des motifs riches en Adénines et Uridines (AU-rich element, ARE), augmente la stabilité et le niveau de traduction de l'ARNm-ARE C/EBPb-beta dans les LAGC ALK+. J'ai également démontré que la tyrosine kinase NPM-ALK augmente l'activité de HuR en modulant ses propriétés biologiques telles que son affinité pour ses ARNm cibles et son recrutement au niveau des polysomes. J'ai enfin déterminé que NPM-ALK et HuR co-localisent dans des granules cytoplasmiques et que HuR est phosphorylée sur résidus tyrosine dans les LAGC ALK+. Dans la deuxième partie de mon travail (manuscrit en préparation), et grâce à la génération d'une série de mutants de HuR, j'ai : 1/ identifié les résidus tyrosine, phosphorylés dans les LAGC ALK+; 2/ démontré l'implication directe de la tyrosine kinase NPM-ALK dans cette phosphorylation; 3/ recherché l'impact de ces phosphorylations sur les propriétés biologiques de HuR (affinité envers ses cibles et localisation subcellulaire). Plus particulièrement, j'ai montré que la phosphorylation du résidu tyr26, localisé dans le motif de reconnaissance aux ARN (RRM1), joue un rôle essentiel dans l'affinité de HuR pour ses ARNm cibles. Il reste aujourd'hui à préciser le rôle de ces phosphorylations dans l'adressage de HuR et de ses cibles aux polysomes. Enfin, il faut démontrer la relevance fonctionnelle de cette phosphorylation sur l'émergence et le maintien des LAGC ALK+. Parallèlement à ce projet qui a été au centre de ma thèse, j'ai également participé à un travail de l'équipe qui a permis de mettre en évidence l'implication de la tyrosine kinase NPM-ALK dans le contrôle de l'expression d'un miRNA, par méthylation de son promoteur. Ce travail s'est basé sur l'exemple du contrôle de l'expression de la protéine anti-apoptotique Mcl1 par le miR-29a. Ces différents travaux sont à l'origine d'une part, de la découverte de deux nouveaux acteurs de la lymphomagénèse dépendante de ALK, l'AUBP HuR et les miRNAs. Ils valident d'autre part le rôle original de NPM-ALK dans la régulation de l'expression génique au niveau post-transcriptionnelThe NPM-ALK chimeric protein is expressed in 75% of Anaplastic Large Cell Lymphomas. Although the oncogenic features of these lymphomas are in part due to the constitutive activation of many signalling pathways such as MAPK, PI3K/AKT, Jak/STAT et PLC-gamma, the identification of new partners of NPM-ALK would allow to consider new molecular mechanisms that could also participate to this phenotype. Thereby, interactions between NPM-ALK and RNA-Binding Proteins (RBPs) led us to postulate that, in addition to its recognized role in transcriptional activation, the oncogenic tyrosine kinase NPM-ALK could also modulate gene expression at the post-transcriptional level. In the first part of my work (1st article), I have shown that HuR, an AU-rich Binding Protein (AUBP), that bind to Adenine and Uridine rich elements (ARE) in the 3' untranslated region of some mRNAs, controls the stability and the level of translation of C/EBP-beta mRNA in ALK+ ALCL. I have also demonstrated that the tyrosine kinase NPM-ALK increases HuR activity by modulating its biological properties such as its binding affinity on its mRNA targets or its recruitment into actively translating polysomes. Lastly, we have determinated that NPM-ALK and HuR colocalize into cytoplasmic granules and that HuR is phosphorylated on tyrosine residus in ALK+ ALCL. In the second part of my work (publication in prep. ), by testing different point mutated versions of HuR, I have: 1/ identified the tyrosine residues that are phosphorylated in ALK+ ALCL; 2/ demonstrated the direct involvement of the tyrosine kinase NPM-ALK in this phosphorylation event; 3/ measured the impact of these phosphorylations on HuR biological properties (affinity toward its targets mRNAs and subcellular localization). More particularly, I have shown that the phosphorylation on tyrosine residue 26 within the RNA recognition motif (RRM) 1 is essential for NPM-ALK-mediated HuR binding to ARE-mRNAs. It remains now to clarify the role of these phosphorylations in the recruitment of HuR into polysomes and to demonstrate the functional relevance of these phosphorylations on the emergence and the maintenance of ALK+ ALCL. In the same time, I have taken part in another work in the team dealing with the role of the tyrosine kinase NPM-ALK in the control of miRNA expression, by methylation events. This project focused on the example of the control of the expression of the anti-apoptotic MCL-1 by miR-29a
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Cholay, Michael. "Identification et caractérisation d'enzymes de déubiquitination impliquées dans les voies de signalisation TGFβ, NF-kB et MAPK." Paris 7, 2009. http://www.theses.fr/2009PA077176.
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La dégradation des protéines est contrôlée chez les eucaryotes par le système ubiquitine/protéasome. Elle est assurée par l'attachement covalent d'une chaîne de poly-ubiquitine aux protéines candidates à la dégradation. Ce mécanisme est impliqué dans différentes fonctions et voies de signalisation cellulaires. La réversibilité de cette réaction a été mise en évidence et elle permet de restaurer une forme biologiquement active des protéines cibles par déubiquitination. Ce mécanisme est assuré, entre autres, par une classe de protéases à cystéine nommée USP (« Ub-specific proteases »). L'objectif de cette étude a été d'identifier les USP impliquées dans la régulation des voies de signalisation TGFp, NF-KB e MARK. Des criblages des USP humaines par interférence à ARN ont été réalisés à l'aide d'essais fonctionnels cellulaires. Ces résultats montrent que les protéines USP1 et USP54 sont impliquées dans la voie de signalisation NF-KB et USP25 dans les voies TGFP et MAPK. Afin d'approfondir les résultats obtenus pour USP25, un criblage par double hybride en levure a permis d'identifier une nouvelle interaction entre USP25 et la kinase SYK. Nous avons démontré que le second domaine SH2 de SYK interagit spécifiquement avec la région C-terminale de USP25 indépendamment de la présence de phosphotyrosine. Cette étude montre que SYK phosphoryle USP25 et altère son niveau d'expression cellulaire. Ainsi, ce programme de recherche a permis d'identifier des enzymes de déubiquitination capables de moduler l'activité de voies de signalisation cellulaires et pourrait à terme conduire à la découverte de mécanismes moléculaires à l'origine de la régulation de l'activité de ces voiesIn eukaryotic cells, the selective degradation of proteins is essentially controlled by the ubiquitin/proteasome System. This degradation is mediated by the covalent linkage of poly-ubiquitin chains on target proteins. This well-established mechanism is involved in a number of cellular functions and signaling pathways. The reversibility of the ubiquitination reaction has been described. This reaction rescues target proteins from degradation by deubiquitination and is catalyzed primarily by a family of cysteine proteases named USP (Ubiquitin-Specific Proteases). The aim of the present study was to identify USP proteins involved in the regulation of the TGFp, NF-KB and MAPK signaling pathways. Systematic screens of human USPs by RNA interference (RNAi) were conducted using cell-based functional assays. The results suggest that USP1 and USP54 are involved in the NF-KB pathway while USP25 is implicated in the TGFP and MAPK pathways. To further understand the function of USP25, a yeast two-hybrid screen was conducted using USP25 as a bait. This screen identifies a novel interaction between USP25 and the SYK tyrosine kinase. We firstly reported that that second SH2 domain of SYK physically interacts with a tyrosine-rich, C-terminal region of USP25 independently of tyrosine phosphorylation. Moreover, we showed that SYK specifically phosphorylates USP25 and alters its cellular levels. To conclude, this study allowed thé identification of ubiquitin-specific proteases able to modulate the activity of important signaling pathways and could ultimately unravel novel molecular mechanisms of regulation of these pathways
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Van, Ziffle Jessica Ann Grant. "Src-family and Syk tyrosine kinases are required for neutrophil effector responses to infection and inflammation." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390082.
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Tanti, Jean-François. "Rôle de la protéine kinase C et de la protéine kinase dépendante de l'AMPc dans la modulation de l'activité tyrosine kinase du récepteur de l'insuline et dans le mécanisme d'action de l'hormone." Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37618785n.
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Russick, Jules. "Traitement de l’hémophilie A à l’aide d’ARNm codant le facteur VIII et prévention de la réponse immunitaire dirigée contre le facteur VIII thérapeutique." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS362.
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L’hémophilie A est une maladie hémorragique rare liée à une absence de facteur VIII (FVIII) fonctionnel de la coagulation. Les formes les plus sévères engendrent l’apparition d’hémorragies spontanées, pouvant mettre en jeu le pronostic vital. La prévention et le traitement des saignements se fait par injection de FVIII thérapeutique. Ce FVIII recombinant est difficile à produire, sa demi-vie est courte et la fréquence des injections impacte la qualité de vie des patients. De plus, chez 25 à 35% d’entre eux, l’injection de FVIII exogène provoque l’apparition d’anticorps anti-FVIII qui neutralisent son activité pro-coagulante et sont donc appelés « inhibiteurs ». Au cours de ma thèse, j’ai tout d’abord validé in vivo une nouvelle stratégie thérapeutique, alternative à la thérapie de substitution et qui repose sur l’injection d’ARNm codant le FVIII (Article 1). Dans le deuxième volet, j’ai étudié la possibilité de prévenir la réponse immunitaire anti-FVIII par inhibition des lymphocytes B. Pour cela, j’ai utilisé un inhibiteur de la Btk, une kinase impliquée dans la voie de signalisation du BCR (Article 2). Enfin, j’ai caractérisé un modèle murin d’hémophilie A humanisé pour le CMH. Ce modèle est déficient en FVIII, en CMH I et II murins et transgénique pour les CMH I et II humains (Article 3). L’ensemble des résultats obtenus pendant ma thèse ouvre la voie à la possibilité d’utiliser une nouvelle technologie (les IVT mRNA) dans le traitement de l’hémophilie A. Mes résultats permettent également d’envisager une nouvelle stratégie pour empêcher l’apparition d’une réponse mémoire anti-FVIII et décrivent un nouveau modèle murin pour l’étude de la réponse immunitaire anti-FVIIIHemophilia A is a rare hemorrhagic disease due to a lack of functional pro-coagulant factor VIII (FVIII). Severe hemophilia A causes spontaneous bleeding and can even lead to death. The prevention and treatment of hemorrhages is achieved by injection of therapeutic FVIII. This treatment is however complicated by its exorbitant cost and the short half-life of FVIII, hampering the patients’ quality of life. Moreover, in 25 to 35% of the patients, the infusion of exogenous FVIII induces the development of anti-FVIII antibodies which inhibit its pro-coagulant activity and are called “FVIII inhibitors”. During my PhD, I first validated in vivo a new therapeutic strategy, alternative to the actual replacement therapy, using a FVIII-encoding mRNA (Article 1). In the second part, I assessed the possibility to inhibit the anti-FVIII immune response by inhibition of B lymphocytes. To do so, I used an inhibitor of Bruton’s tyrosine kinase (Btk), a kinase involved in the signalling pathway of the receptor of B cells (BCR)(Article 2). Finally, I characterized an hemophilia A mouse model, humanized for MHC. This model lacks FVIII as well as mouse MHC class I and II expression and is transgenic for human MHC I and II. The results obtained during my PhD validate the use of in vitro transcribed mRNA technology for hemophilia A treatment. They also provide a new strategy to inhibit the memory immune response against FVIII and describe a novel mouse model for studying anti-FVIII immune responses
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Blazar, Ilyse Natasha. "Differential effects of epidermal growth factor receptor inhibitors on glioblastoma multiforme." Thesis, 2015. https://hdl.handle.net/2144/16128.
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OBJECTIVE: Glioblastoma Multiforme (GBM), one of the most malignant forms of primary brain tumors, is characterized by its highly heterogenous genetic composition, aggressive infiltration of surrounding tissue, and resistance to current treatments. Gene expression analysis has characterized GBM into four main types, with a significant portion belonging to the Classical subtype, typified by overexpression and/or mutation of the epidermal growth factor receptor (EGFR). Also common to this subtype of GBM is the loss of crucial tumor suppressor genes Ink4A/ARF and PTEN, which contribute to the invasive nature and unregulated proliferation that underlie the GBM pathology. The high rate of tumor recurrence post treatment with surgical resection, chemotherapy, and radiation has driven the pursuit of more effective molecularly targeted therapies. This study was undertaken to determine the effects of two types of small molecule tyrosine kinase inhibitors on cells overexpressing wild-type EGFR in the context of their respective complements of tumor suppressor genes.
METHODS: Several cell lines were established from mouse models of EGFR wild-type (EGFRWT) driven gliomagenesis and treated with 10 μM of type I tyrosine kinase inhibitors Gefitinib (Iressa®, Astra Zeneca), CI-1033 (Canertinib, Pfizer), or Dimethyl Sulfoxide vehicle. Cells were exposed to each drug treatment as part of a time course ranging from 0 to 24 hours and then evaluated by trypan blue exclusion and Western blot analysis for cell viability and molecular and biochemical effects respectively.
RESULTS: Evaluation of cell viability indicated that CI-1033 caused a greater increase in cell death than gefitinib when compared to control treated cells regardless of the tumor suppressors lost. Gefitinib was found to cause cell death only in cells expressing the PTEN tumor suppressor whereas CI-1033 showed similar levels of cell death for cells deficient in Ink4A/ARF or both Ink4A/ARF and PTEN tumor suppressors. Western blot analysis revealed that CI-1033 more effectively inhibited EGFR compared to gefitinib. Treatment with both gefitinib and CI-1033 effectively blocked phosphorylation of EGFR, but this effect was less pronounced with gefitinib treatment. Further analysis of downstream signaling molecules showed a greater presence of cleaved caspase 3, a hallmark of apoptosis, in gefitinib treated cells expressing PTEN than in those cells treated with CI-1033. Cells deficient in both Ink4A/ARF and PTEN did not demonstrate any induction of cleaved caspase 3 following either treatment.
CONCLUSIONS: Based on the significant differences in cell viability between treatments, CI-1033 is an overall more effective inhibitor of EGFRWT expressing cells lacking PTEN, while gefitinib and CI-1033 were found to be similarly effective in cells expressing PTEN. The results of western blot analysis indicate that total and irreversible EGFR inhibition may be necessary to induce cell death in a manner that effectively terminates downstream cell signaling. It is likely that CI-1033, unlike gefitinib, induces apoptosis in a caspase-independent manner, which may be one of the many differences in downstream effects produced by these two drugs. Further research is necessary to determine the extent to which each inhibitor shuts down proliferative cell signaling pathways such as PI3K-AKT and MEK-ERK signaling pathways downstream of EGFR. Overall, these data indicate that genotype plays an important role in the determination of therapeutic response and may aid in the evaluation of clinical prognoses.
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Chien, Han-Sheng, and 錢漢聲. "ManC, Gnd and KpUgd are phosphorylated by tyrosine kinase, KpWzc of Klebsiella pneumoniae-Kinetic analysis of ManC and Gnd, identification of phosphotyrosine residues of KpUgd and search for other phosphorylation target." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/24301281403613914274.
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碩士國立清華大學
分子醫學研究所
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克雷白氏肺炎桿菌為一株伺機性引起院內感染疾病的格蘭氏陰性菌，其外部包覆著由多醣體所組成的厚莢膜。此一莢膜可以讓細菌逃避細胞的吞噬作用以及避免被血清因子所毒殺。在實驗室之前的研究中，證明了剔除酪胺酸激酶的基因KpWzc會明顯地減少其原本所具有的黏性和莢膜多醣體的量。證實了克雷白氏肺炎桿菌蛋白質酪胺酸激酶KpWzc夠將克雷白氏肺炎桿菌中的KpUgd、Gnd和ManC這三個酵素磷酸化。而磷酸化對KpUgd酵素活性有顯著提升。本實驗目的在驗證蛋白質酪胺酸激酶KpWzc對其下游磷酸化蛋白質Gnd, ManC之酵素活性影響以及尋找KpUgd被磷酸化之酪胺酸殘基。ManC 是一個雙功能酵素，前半段具有磷酸甘露糖異位轉化酶活性，後半段則具有磷酸甘露糖異構酶活性，而Gnd 具有磷酸葡萄糖酸去氫酶活性，過量表現與被純化的兩個酵素先經由牛小腸鹼性去磷酸酶處理後，與蛋白質酪胺酸激酶KpWzcE23進行磷酸化反應，並測試期專有酵素活性，結果顯示兩個酵素的三個酵素最大反應速率皆有上升。在此研究之中，我們亦構築了四段截短的KpUgd片段，用以探討磷酸酪胺酸殘基位置，同位素放射能照像結果顯示，四段皆有被偵測到磷酸化訊號，證明蛋白質酪胺酸激酶KpWzcE23可同時對KpUgd上多個酪胺酸殘基進行磷酸化。另外，我們也用磷酸化蛋白質體學技術來尋找細菌內其他可能被磷酸化的蛋白質，但是並沒有找到可能的磷酸化蛋白質。以上實驗結果可推測KpUgd, ManC與Gnd三個酵素皆參與由蛋白質酪胺酸激酶KpWzc調控之莢膜多醣體合成。
Books on the topic "Arg tyrosine kinase"
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Hodgkiss, Andrew. Introduction to cancer biology. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198759911.003.0001.
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A brief introduction to cancer biology, aimed at psychiatrists, is offered. Selective DNA transcription, the cell cycle, receptor tyrosine kinases, and cell signalling pathways are introduced, using the EGFR/RAS/MAPK pathway as an exemplar. The molecular pathology of oncogenesis is summarized, including discussion of oncogenes, tumour suppressor genes, and examples of driver mutations. The exploitation of such mutations in stratified medicine, using molecularly targeted agents, is mentioned. Finally, Hanahan and Weinberg’s six hallmarks of cancer are listed, adding angiogenesis and metastasis to the picture of oncogenesis.
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Fleischmann, Roy. Signalling pathway inhibitors. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0081.
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Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and SyK pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Tofacitinib is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2 while baricitinib (formerly INCB028050) predominantly inhibits JAK1/2. Many of the proinflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Fostamatinib disodium is an orally available inhibitor of spleen tyrosine kinase (SyK), which is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling may interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib has been investigated in multiple phase 2 and phase 3 trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα) and in patients who have failed TNFα inhibitors. The efficacy of fostamatinib and baricitinib has been investigated in phase 2 trials; both are in large phase 3 clinical programmes. Each of these medications has demonstrated efficacy; their safety profile has been shown to be different from each other and from currently approved biological agents. This chapter discusses what is currently known and understood about their efficacy and safety.
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Eisen, Tim. The patient with renal cell cancer. Edited by Giuseppe Remuzzi. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0172.
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Renal cancer is the commonest malignancy of the kidney and worldwide, accounts for between 2% and 3% of the total cancer burden. The mainstay of curative treatment remains surgery. There have been significant advances in surgical technique, the most important ones being nephron-sparing surgery and laparoscopic nephrectomy. The medical treatment of advanced renal cell cancer has only improved markedly in the last decade with the development of antiangiogenic tyrosine-kinase inhibitors, inhibitors of mammalian target of rapamycin, and a diminished role for immunotherapy.Tyrosine-kinase inhibitor therapy results in reduction of tumour volume in around three-quarters of patients and doubles progression-free survival, but treatment is not curative. The management of side effects in patients on maintenance tyrosine-kinase inhibitors has improved in the last 3 years, although still presents difficulties which have to be actively considered.The molecular biology of renal cell carcinoma is better understood than for the majority of solid tumours. The commonest form of renal cancer, clear-cell carcinoma of the kidney, is strongly associated with mutations in the von Hippel–Lindau gene and more recently with chromatin-remodelling genes such as PBRM1. These genetic abnormalities lead to a loss of control of angiogenesis and uncontrolled proliferation of tumour cells. There is a very wide spectrum of tumour behaviour from the extremely indolent to the terribly aggressive. It is not currently known what accounts for this disparity in tumour behaviour.A number of outstanding questions are being addressed in scientific and clinical studies such as a clearer understanding of prognostic and predictive molecular biomarkers, the role of adjuvant therapy, the role of surgery in the presence of metastatic disease, how best to use our existing agents, and investigation of novel targets and therapeutic agents, especially novel immunotherapies.
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McCann, Shaun R. Leukaemia. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198717607.003.0007.
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The word leukaemia still is associated with foreboding and a fear of premature death. Steady advances have been made in the treatment of childhood leukaemia but, with notable exceptions, the same is not true in adults. The so-called genetic/molecular revolution has extended the understanding of the pathogenesis of many forms of leukaemia but, as yet, has rarely facilitated cure. With the introduction of tyrosine kinase inhibitor therapy, chronic myeloid leukaemia is the obvious exception but it still needs to be seen as to whether the cytogenetic/molecular revolution can provide cures for many elderly patients with leukaemia, as such patients respond poorly to chemotherapy. Haematopoietic stem cell transplantation, although toxic, expensive, and difficult, still provides a cure for many patients. In spite of all these advances, however, most adults with acute leukaemia or myelodysplastic syndrome are destined to die from their disease, and the causes of these fatal illnesses continue to elude researchers.
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Stafstrom, Carl E., and Thomas P. Sutula. 2-Deoxyglucose. Edited by Dominic P. D’Agostino. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190497996.003.0036.
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Metabolic regulation of excitability is increasingly appreciated as a strategy to control seizures and reduce pathogenesis. Inhibiting or bypassing glycolysis may be one way in which the ketogenic diet suppresses seizures. 2-deoxy-D-glucose (2DG) is a glucose analog that partially inhibits glycolysis and has antiseizure effects in several acute and chronic seizure models. The mechanisms underlying the acute and chronic effects of 2DG are being investigated. Preliminary studies provide evidence that the acute anticonvulsant actions of 2DG involve activity-dependent presynaptic suppression of excitatory synaptic transmission during network synchronization. The chronic effects of 2DG entail reduction of the expression of brain-derived neurotrophic factor and its receptor, tyrosine kinase B. Preclinical toxicology studies demonstrate that 2DG has a favorable toxicity profile at doses effective for seizure protection. Currently available preclinical studies support 2DG as a novel first-in-class metabolic treatment for epilepsy with an antiglycolytic mechanism distinct from all other anticonvulsants.
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Kuwabara, Satoshi. Neuromuscular junction disorders. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199658602.003.0014.
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Ten seminal papers on disorders of the neuromuscular junction are described, covering historical aspects, recent advances in immunological, biological, and genetic researches, and future perspectives. Early descriptions of myasthenia gravis (MG) date back to the seventeenth century, and MG acquired its name in the nineteenth century. The first symptomatic treatment with cholinesterase inhibitors was reported in 1934, leading to the development of modern immunological therapies. Following the discovery of anti-MuSK (muscle-specific tyrosine kinase) antibody in 2001, MG is currently classified into three categories: AChR-positive, MuSK-positive, and dual-seronegative. Lambert-Eaton myasthenic syndrome was recognized in 1956, followed by the discovery of antibodies to voltage-gated calcium channels in the pre-synaptic membrane, facilitating diagnosis and improving the understanding of the pathophysiological mechanisms. Since the late twentieth century, many types of congenital myasthenic syndromes with pre-synaptic, synaptic, and post-synaptic defects have been identified, and a classification based on molecular genetics is in evolution.
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Cassidy, Jim, Donald Bissett, Roy A. J. Spence OBE, Miranda Payne, and Gareth Morris-Stiff. Bone and soft tissue malignancies. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199689842.003.0025.
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Haematological malignancies examines the epidemiology, genetics, clinical presentation and classification of these diseases, and presents current treatment approaches for each. First are the acute leukaemias, and the management of acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Chronic myeloid leukaemia, its genetics and sensitivity to tyrosine kinase inhibitors, is described. Myelodysplastic syndromes and their management, are followed by chronic lymphoid leukaemias, a large heterogeneous group of diseases, and their treatment. Hodgkin lymphoma, its pathology and presentation, staging and role of PET scanning, is described along with current treatment with chemotherapy and limited radiotherapy. Non-Hodgkin lymphoma is another heterogeneous group of diseases, divided into low-grade and high-grade pathology, and varying in their genetics, presentation, and management. Rituximab is a key component of chemotherapy regimens against B-cell lymphoma. Myeloma and other plasma cell dyscrasias are described, and treatment options reviewed. Myeloma remains incurable, but with appropriate management consistent with prolonged good quality life. Treatment includes chemotherapy, bisphosphonate therapy, analgesics and radiotherapy, Throughout this chapter is emphasised the importance of clinical trials in driving the rapid improvements in treatment of these diseases.
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Reddy, Ugan, and Nicholas Hirsch. Diagnosis, assessment, and management of myasthenia gravis and paramyasthenic syndromes. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0244.
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Diseases that affect the neuromuscular junction (NMJ) interfere with normal nerve transmission and cause weakness of voluntary muscles. The two most commonly encountered are acquired myasthenia gravis (MG) and the Lambert–Eaton myasthenic syndrome (LEMS). Acquired MG is an autoimmune disease in which antibodies are directed towards receptors at the NMJ. In 85% of patients, IgG antibodies against the postsynaptic acetylcholine receptor (AChR) are found (seropositive MG). The thymus gland appears to be involved in the production of these which cause an increase rate of degradation of AChR resulting in a decreased receptor density resulting in a reduced postsynaptic end-plate potential following motor nerve stimulation and leading to muscle weakness. Although all voluntary muscles can be affected, ocular, bulbar, respiratory, and proximal limb weakness predominates. In the majority of seronegative patients, an antibody directed towards a NMJ protein called muscle specific tyrosine kinase (MUSK) is found. Anti-MUSK MG is characterized by severe bulbar and respiratory muscle weakness. Diagnosis of MG requires a high degree of clinical suspicion coupled with pharmacological and electrophysiological testing, and detection of the various causative antibodies. Treatment of MG involves enhancing neuromuscular transmission with long-acting anticholinesterase agents and immunosuppression. Acute exacerbations are treated with either plasma exchange or intravenous immunoglobulin. Myasthenic crisis is associated with severe muscle weakness that necessitates tracheal intubation and mechanical ventilation. LEMS is an autoimmune disease in which IgG antibodies are directed towards the pre-synaptic voltage-gated calcium channels at the NMJ. It is often associated with malignant disease (usually small cell carcinoma of the lung). Autonomic dysfunction is prominent and patients show abnormal responses to neuromuscular blocking drugs.
Book chapters on the topic "Arg tyrosine kinase"
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Sato, Ken-ichi. "Fertilization and Protein Tyrosine Kinase Signaling: Are They Merging or Emerging?" In Diversity and Commonality in Animals, 569–89. Tokyo: Springer Japan, 2018. http://dx.doi.org/10.1007/978-4-431-56609-0_27.
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Van Obberghen, E., S. Gammeltoft, Y. Le Marchand-Brustel, and R. Ballotti. "Insulin Receptor: Role of Receptor Tyrosine Kinase in Insulin Signalling and Action." In Bayer AG Centenary Symposium, 73–81. Berlin, Heidelberg: Springer Berlin Heidelberg, 1989. http://dx.doi.org/10.1007/978-3-642-74255-2_6.
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Stanley, E. Richard, Yee-Guide Yeung, Karen L. Berg, and Fiona J. Pixley. "Studies of the very Early Responses of a Receptor Tyrosine Kinase to Growth Factor Binding and their Application to the Purification and Identification of Proteins that are Tyrosine Phosphorylated in the Growth Factor Response." In Tyrosine Phosphorylation/Dephosphorylation and Downstream Signalling, 45–62. Berlin, Heidelberg: Springer Berlin Heidelberg, 1993. http://dx.doi.org/10.1007/978-3-642-78247-3_4.
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Carrera, Ana C., Carrie L. Baker, Thomas M. Roberts, and Drew M. Pardoll. "The Tyrosine Kinases pp561ck and pp59fyn are Activated in Thymocytes Undergoing Positive Selection." In Progress in Immunology Vol. VIII, 893–99. Berlin, Heidelberg: Springer Berlin Heidelberg, 1993. http://dx.doi.org/10.1007/978-3-642-51479-1_114.
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Singh, Pushpendra, Shashank Kumar, and Felix Bast. "Natural Compounds Are Smart Players in Context to Anticancer Potential of Receptor Tyrosine Kinases: An In Silico and In Vitro Advancement." In Translational Bioinformatics and Its Application, 177–202. Dordrecht: Springer Netherlands, 2017. http://dx.doi.org/10.1007/978-94-024-1045-7_8.
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Shechter, Yoram, Jingping Li, Joseph Meyerovitch, Dov Gefel, Rafael Bruck, Gerard Elberg, David S. Miller, and Assia Shisheva. "Insulin-like actions of vanadate are mediated in an insulin-receptor-independent manner via non-receptor protein tyrosine kinases and protein phosphotyrosine phosphatases." In Vanadium Compounds: Biochemical and Therapeutic Applications, 39–47. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4613-1251-2_5.
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Kursunluoglu, Gizem, Duygu Erdogan, Elcin Cagatay, Esra Bulut Atalay, Seminay Guler, Yonca Gungor, and Hulya Ayar Kayali. "The Role of Kinase Inhibitors in Cancer Therapies." In Protein Kinases - Promising Targets for Anticancer Drug Research. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99070.
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Protein kinases are enzymes that transfer a phosphate group to the threonine, serine, or tyrosine residues of the target protein, regulating its activity. The activity of these enzymes are very important and strictly regulated in the cell as they promote cell proliferation, survival, and migration. In the case of any dysregulation of these enzymes, they can be associated with cancer initiation and progression. Small-molecule kinase inhibitors approved by the FDA for their improved clinical benefits are currently used in targeted therapy for the treatment of various cancers. So far, there are 62 FDA-approved therapeutic agents targeting different protein kinases, eight of which were approved in 2020. Today, kinase inhibitors are used as FDA approved cancer agents and newly developed ones are evaluated in clinical trials. Those protein kinase inhibitors can be grouped as growth factor receptor inhibitors, Ras/Raf/Mek inhibitors, phosphoinositide 3-kinase (PI3K) and cyclin dependent kinase inhibitors, other targets, and agents such as protein kinase c and 3 phosphoinositide-dependent kinase 1. In this chapter, these kinases, their pathways, and their inhibitors will be discussed in detail.
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Bhuyan, Biswajit, Somanath Padhi, Probodha Kumar Das, and Chinmayee Panigrahi. "Chronic Myeloid Leukemia: Biology, Diagnosis, and Management." In Leukemia - From Biology to Diagnosis and Treatment [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.108334.
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Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm characterized by florid myelo-megakaryocytic proliferation involving peripheral blood, bone marrow, and spleen. These results are due to balanced reciprocal translocation between long arm of chromosome 9 and 22 that produces a truncated chromosome 22 (Philadelphia chromosome) leading to fusion of BCR-ABL1 genes causing enhanced autonomous activation of tyrosine kinase and downstream cellular proliferation pathway. While targeted therapy with novel tyrosine kinase inhibitors (TKI) has revolutionized the outcome in such patients, occurrence of additional cytogenetic abnormalities, emergence of TKI resistance, and idiosyncratic marrow suppression following higher generation TKI therapy have posed newer management challenges in CML. This chapter is aimed to highlight the recent updates in the disease biology, stepwise diagnostic work-up, and management guidelines in CML with a brief highlight on the prospect of stem cell transplantation in such condition.
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Khoo, B., T. M. Tan, and S. R. Bloom. "Pancreatic endocrine disorders and multiple endocrine neoplasia." In Oxford Textbook of Medicine, edited by Mark Gurnell, 2449–63. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0258.
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Pancreatic neuroendocrine tumours (islet-cell tumours) are rare and usually sporadic, but they may be associated with complex familial endocrine cancer syndromes. Recognized types of pancreatic neuroendocrine tumours are those that are non-functioning (often advanced at diagnosis and presenting with mass effects due to the absence of symptoms attributable to hormone hypersecretion), insulinoma (the most frequent type), and others including gastrinoma, VIPoma, and glucagonoma. The following should be considered in addition to the symptomatic treatments: surgical resection—the only curative treatment, but not possible in many cases; tyrosine kinase inhibitors which inhibit specific kinases involved in tumour cell proliferation, growth, and angiogenesis; mammalian Target of Rapamycin (mTOR) inhibitors; peptide-receptor radionuclide therapy (radiolabelled somatostatin analogues).
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Kushwaha, Bhawna, Rohit Beniwal, Aradhana Mohanty, Ajay Kumar Singh, Raj Kumar Yadav, and Satish Kumar Garg. "Effect of Heavy Metals on Tyrosine Kinases Signaling during Sperm Capacitation." In Infertility and Assisted Reproduction [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99261.
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Sperm capacitation is the key event prior to fertilization. Success rate of currently used assisted reproductive technology like in-vitro fertilization is 50% dependent on sperm maturation or capacitation. In-vivo capacitation occur almost in female reproductive tract in response to various signaling or enzymatic molecules. Interestingly, both early and late events of capacitation are centrally regulated by protein kinase A (PKA). Influx of Ca2+ and HCO3-transmembrane drive leads to change in pH and intracellular cAMP which ultimately activate PKA regulated capacitation. PKA phosphorylates several target proteins that are presumed to initiate different signaling pathways. Some divalent heavy metals like lead, mercury, arsenic and cadmium mimic Ca++ entry and its functions and ultimately affect capacitation by inhibiting or inducing tyrosine phosphorylation. In this chapter we review the mechanism of heavy metals by which they affect the tyrosine phosphorylation during sperm capacitation.
Conference papers on the topic "Arg tyrosine kinase"
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Chen, Jing, Taro Hitosugi, Jun Fan, Sumin Kang, Ting-Lei Gu, and Titus Boggon. "Abstract 997: Oncogenic tyrosine kinases are localized to mitochondria and regulate cancer metabolism by phosphorylating key components of pyruvate dehydrogenase kinase complex." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-997.
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Sodani, Kamlesh, Ye-Hong Kuang, Tong Shen, Saurabh Vispute, Amit K. Tiwari, Yu Lei, Jeferson Lee, Xiang Chen, Charles R. Ashby, and Zhe-Sheng Chen. "Abstract 1519: Tyrosine kinase inhibitors are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1519.
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Williams, Raven A., Joakin Mori, Hui-Xian Lin, Alahni Becks, Clayton Yates, and Honghe Wang. "Abstract 1331: Receptor tyrosine kinases are differentially phosphorylated in metastatic castration resistant prostate cancer." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-1331.
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Williams, Raven A., Joakin Mori, Hui-Xian Lin, Alahni Becks, Clayton Yates, and Honghe Wang. "Abstract 1331: Receptor tyrosine kinases are differentially phosphorylated in metastatic castration resistant prostate cancer." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-1331.
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Sfondouris, Mary E., Jayalakshmi Sridhar, Cheryl Stevens, and Frank Jones. "Abstract B058: Drug resistant HER2Δ16 overexpression cells are sensitive to a new class of tyrosine kinase inhibitors." In Abstracts: AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications - October 3-6, 2013; San Diego, CA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1557-3125.advbc-b058.
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LeDuc, Philip R. "Dynamic Formation for the Mechanical Connection of Focal Adhesion Complexes to Study Localized Mechanisms of Angiogenesis Through Modeling With Cellular Automata." In ASME 2001 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2001. http://dx.doi.org/10.1115/imece2001/bed-23159.
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Abstract The mechanical connection through the formation of focal adhesion complexes (FACs) is critical in cell growth and apoptosis. The FACs act between the cells and the extracellular matrix (ECM), which in turn influences angiogenesis, the growth of new capillary blood vessels [1]. These complexes form direct connections from ECM into the cell cytoskeleton through a series of protein binding events. This linkage is critical for mechanical force sensing and mechanotransduction signaling [2]. Here, the probabilistic modeling of this complex formation is undertaken to begin to uncover the effect of the spatial distribution and temporal effects on this dynamic process. In this, the rich dynamic process of the FACs formation through the binding events of integrin, paxillin, talin, and vinculin are examined. The FACs are mediated through the clustering of transmembrane integrins, which initiate the binding cascade. This interaction has been shown to be a critical event in the activation of the mechanochemical cascade and further mediates downstream signaling of protein tyrosine kinases including focal adhesion kinase [3].
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Sakai, Kazuko, Tokuzo Arao, Kazuyuki Furuta, Tomoyuki Nagai, Kanae Kudo, Hiroyasu Kaneda, Daisuke Tamura, et al. "Abstract 3994: Expression levels of EGFR-ligands are up-regulated in EGFR tyrosine kinase inhibitor-resistant cell line." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3994.
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Ebi, Hiromichi, Hiroshi Kotani, and Seiji Yano. "Abstract 749: Both amplification and protein expression are required to predict FGFR tyrosine kinase inhibitor sensitivity in lung cancer." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-749.
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Sheetz, M. P. "Local Force on Cell Cytoskeletons Causes Binding of Focal Contact Proteins Dependent Upon Tyrosine Phosphatase/Kinases." In ASME 2001 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2001. http://dx.doi.org/10.1115/imece2001/bed-23074.
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Abstract Cellular responses to mechanical force are critical for the shaping of cells and for many physiological functions that need to be satisfied in functionally engineered tissues. From several recent observations, there is the suggestion that physical force developed by a cell or its environment can signal to the cell through oncogenic tyrosine kinase/phosphatase pathways and alter the program of the cell. These responses occur in seconds and lead to the localization of focal contact proteins at the sites of maximum force on the cytoskeleton. We suggest that forces directly applied to cytoskeleton proteins cause the activation of the cellular responses.
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Tarantelli, Chiara, Eugenio Gaudio, Andrea Unzue, Pawel Sledz, Hillarie Ekeh, Elena Bernasconi, Filippo Spriano, Cristina Nevado, Amedeo Caflisch, and Francesco Bertoni. "Abstract B182: The novel tyrosine kinase inhibitors UJ26 and UJ30 are active in solid tumor and hematologic cancer cell lines." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; October 26-30, 2017; Philadelphia, PA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1535-7163.targ-17-b182.
Full textReports on the topic "Arg tyrosine kinase"
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Zheng, Jiaxi, and Haihua Yang. Clinical Benefits of Immune Checkpoint Inhibitors and Predictive Value of Tumor Mutation Burden in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, January 2022. http://dx.doi.org/10.37766/inplasy2022.1.0008.
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Review question / Objective: Is immunotherapy associated with beneficial clinical outcomes for hepatocellular carcinoma (HCC) and how can combination immunotherapy be deployed to produce the best benefit? Is tumor mutation burden (TMB) a predictive biomarker for immune‐checkpoint inhibitors? Condition being studied: To this date, about 50 single-arm clinical trials and several randomized control trials (RCTs) presented final or interim results of investigations on the efficacy of PD-1/PD-L1 inhibitors for advanced HCC. In the CheckMate 459, IMbrave 050, and ORIENT-32, immunotherapies were found to significantly improve progression-free survival (PFS) and overall survival (OS) compared with sorafenib (a tyrosine-kinase inhibitor, as standard systemic treatment) in patients with advanced hepatocellular carcinoma. However, these clinical trials were different on clinical phases, sample size, and response evaluation criteria, and inconsistent clinical outcomes were shown in several trials.
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Song, Yaowen, Shuiyu Lin, Jun Chen, Silu Ding, and Jun Dang. First-line treatment with TKI plus brain radiotherapy vs TKI alone in EGFR-mutated non-small-cell lung cancer with brain metastases: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, January 2023. http://dx.doi.org/10.37766/inplasy2023.1.0013.
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Review question / Objective: It remains uncertain whether first-line treatment with upfront brain radiotherapy (RT) in combination with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is superior to EGFR-TKIs alone in EGFR-mutated non-small-cell lung cancer with newly diagnosed brain metastases (BMs). We performed a meta-analysis to address this issue. Condition being studied: Brain radiotherapy (RT) has been shown to damage the blood-brain barrier (BBB) and improve the concentration of EGFR-TKIs in the CSF. Additionally, RT can result in a reduction of EGFR-TKIs resistance. Therefore, EGFR-TKIs in combination with brain RT should be more effective than EGFR-TKIs alone theoretically. However, results from retrospective studies are inconsistent. There is the possibility that patients characteristics or brain RT technique affect the efficacy of treatments. To date, there is still no randomized controlled trials (RCTs) comparing the two treatment strategies.