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https://www.readbyqxmd.com/read/28454278/the-associated-pyrazolopyrimidines-pp1-and-pp2-inhibit-protein-tyrosine-kinase-6-activity-and-suppress-breast-cancer-cell-proliferation
#1
Hyun Jae Shim, Han Ie Kim, Seung-Taek Lee
Protein tyrosine kinase (PTK)6, also known as breast tumor kinase, is a non-receptor tyrosine kinase. It is closely associated with, but evolutionarily distinct from, the Src family members. PTK6 has a role in proliferation, migration and invasion in various cancers, and therefore has been suggested as a potentially valuable therapeutic target. In an attempt to develop PTK6 inhibitors, chemicals known to inhibit various kinases were screened for their ability to inhibit PTK6. Pyrazolopyrimidine (PP)1, PP2 and a lymphocyte-specific protein tyrosine kinase inhibitor strongly inhibited the catalytic activity of PTK6 in vitro...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28453902/lighting-up-kinase-action-in-platelets
#2
Albert Smolenski
Platelet functions are highly regulated by signaling networks involving at least 300 protein kinases [2]. Platelets express members of the mitogen-activated protein kinase (MAPK) family including p42 ERK2 and, at lower concentrations, p44 ERK1. Both ERK isoforms are activated by agonists like von Willebrand factor, collagen, thrombin, ADP and thromboxane A2 [3-7]. ERK activation depends on MAPK kinase (MKK-1 or MEK) and involves Gq, Gi, phospholipase C and Src family kinase signaling [5, 8]. Active ERK has been shown to stimulate thromboxane A2 production [5] and to contribute to platelet aggregation [4, 9]...
April 28, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28447863/lysophosphatidic-acid-and-amitriptyline-signal-through-lpa1r-to-reduce-p-glycoprotein-transport-at-the-blood-brain-barrier
#3
David B Banks, Gary Ny Chan, Rebecca A Evans, David S Miller, Ronald E Cannon
The blood-brain barrier is a microvascular network that (1) provides neuroprotection from metabolic and environmental toxins and (2) limits the delivery of therapeutics to the central nervous system (CNS). The ATP-binding cassette transporter P-glycoprotein contributes to the latter by actively pumping clinical substrates back into circulation before they can reach the brain parenchyma. Targeting P-glycoprotein has proven effective in increasing the delivery of therapeutics to their cerebral targets. We provide a novel mechanism to achieve this end in functioning, intact rat brain capillaries, whereby the bioactive phospholipid lysophosphatidic acid (LPA) and tricyclic antidepressant (TCA) amitriptyline reduce basal P-glycoprotein transport activity through a distinct lysophosphatidic acid 1 receptor-mediated signaling cascade that requires G-protein coupling, Src kinase, and ERK 1/2...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28446239/dasatinib%C3%A2-%C3%A2-gefitinib-a-non-platinum-based-combination-with-enhanced-growth-inhibitory-anti-migratory-and-anti-invasive-potency-against-human-ovarian-cancer-cells
#4
Benoît Thibault, Bertrand Jean-Claude
BACKGROUND: Ovarian cancer is the leading cause of death for gynecological cancers and the 6th cause of women cancer death in developed countries. The late stage detection, the peritoneal dissemination and the acquisition of resistance against carboplatin are the main reasons to explain this poor prognosis and strengthen the need of alternative treatments to improve the management of ovarian cancer and/or to sensitize tumors to platinum salts. Epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (Met) and cellular Src kinase (c-Src) are crucial kinases implied in ovarian tumor growth, survival, invasion and resistance to carboplatin...
April 26, 2017: Journal of Ovarian Research
https://www.readbyqxmd.com/read/28445138/killer-cell-immunoglobulin-like-receptor-2dl4-is-expressed-in-and-suppresses-the-cell-growth-of-langerhans-cell-histiocytosis
#5
Yusuke Takei, Chiyuki Ueshima, Tatsuki R Kataoka, Masahiro Hirata, Akihiko Sugimoto, Mariyo Rokutan-Kurata, Koki Moriyoshi, Kazuo Ono, Ichiro Murakami, Sanju Iwamoto, Hironori Haga
Killer cell immunoglobulin-like receptor (KIR) 2DL4 (CD158d) is a receptor for human leukocyte antigen-G. The function of KIR2DL4 has been reported in human natural killer cell lymphoma and mastocytosis, but not in Langerhans cell histiocytosis (LCH). Herein, we examined the expression and function of KIR2DL4 in LCHs. In pathological specimens, 27 of 36 LCH cases (75.0%) were immunohistochemically positive for KIR2DL4. Its expression was independent of age, gender, location, multi- or single-system, and the status of BRAFV600E immunostaining...
April 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28444899/tumour-vascular-leakage-defect-due-to-endothelium-targeted-fak-kinase-dead-mutation-is-abrogated-by-fak-y397e-expression
#6
Annika N Alexopoulou, Delphine M Lees, Natalia Bodrug, Tanguy Lechertier, Isabelle Fernandez, Gabriela D'Amico, Matthew Dukinfield, Silvia Batista, Bernardo Tavora, Bryan Serrels, Kairbaan Hodivala-Dilke
Focal adhesion kinase (FAK) inhibitors have been developed as potential anti-cancer agents and are in clinical trials. In vitro activation of FAK kinase domain triggers autophosphorylation of tyrosine 397 (Y397), Src activation and subsequent phosphorylation of other FAK tyrosine residues. However, how FAK-Y397 mutations affect FAK-kinase-dead phenotypes in tumour angiogenesis in vivo is unknown. We developed three Pdgfb-iCre(ert) -driven endothelial-cell (EC)-specific, tamoxifen-inducible homozygous mutant mouse lines: FAK wild-type (WT), FAK kinase-dead (KD), and double mutant (DM); KD with a putatively phosphomimetic Y397E mutation...
April 26, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28442050/lonidamine-ethyl-ester-mediated-remodelling-of-the-sertoli-cell-cytoskeleton-induces-phosphorylation-of-plakoglobin-and-promotes-its-interaction-with-%C3%AE-catenin-at-the-blood-testis-barrier
#7
Dolores D Mruk, Michele Bonanomi, Bruno Silvestrini
Several compounds affect male fertility by disrupting the adhesion of germ cells to Sertoli cells, which results in the release of undeveloped germ cells into the seminiferous tubule lumen that are incapable of fertilising the ovum. Indazole carboxylic acids are one class of compounds exhibiting such effects and they have been investigated as non-hormonal contraceptives for potential human use. The aims of this study were to investigate the effects of lonidamine-ethyl ester, an indazole carboxylic acid, on spermatogenesis and cell junctions, in particular, desmosomes...
April 2017: Reproduction, Fertility, and Development
https://www.readbyqxmd.com/read/28439006/murine-model-indicates-22q11-2-signaling-adaptor-crkl-is-a-dosage-sensitive-regulator-of-genitourinary-development
#8
Meade Haller, Qianxing Mo, Akira Imamoto, Dolores J Lamb
The spectrum of congenital anomalies affecting either the upper tract (kidneys and ureters) or lower tract (reproductive organs) of the genitourinary (GU) system are fundamentally linked by the developmental origin of multiple GU tissues, including the kidneys, gonads, and reproductive ductal systems: the intermediate mesoderm. Although ∼31% of DiGeorge/del22q11.2 syndrome patients exhibit GU defects, little focus has been placed on the molecular etiology of GU defects in this syndrome. Among del22q11.2 patients exhibiting GU anomalies, we have mapped the smallest relevant region to only five genes, including CRKLCRKL encodes a src-homology adaptor protein implicated in mediating tyrosine kinase signaling, and is expressed in the developing GU-tract in mice and humans...
April 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28434868/hif-1%C3%AE-dependent-wound-healing-angiogenesis-in%C3%A2-vivo-can-be-controlled-by-site-specific-lentiviral-magnetic-targeting-of-shp-2
#9
Yvonn Heun, Kristin Pogoda, Martina Anton, Joachim Pircher, Alexander Pfeifer, Markus Woernle, Andrea Ribeiro, Petra Kameritsch, Olga Mykhaylyk, Christian Plank, Florian Kroetz, Ulrich Pohl, Hanna Mannell
Hypoxia promotes vascularization by stabilization and activation of the hypoxia inducible factor 1α (HIF-1α), which constitutes a target for angiogenic gene therapy. However, gene therapy is hampered by low gene delivery efficiency and non-specific side effects. Here, we developed a gene transfer technique based on magnetic targeting of magnetic nanoparticle-lentivirus (MNP-LV) complexes allowing site-directed gene delivery to individual wounds in the dorsal skin of mice. Using this technique, we were able to control HIF-1α dependent wound healing angiogenesis in vivo via site-specific modulation of the tyrosine phosphatase activity of SHP-2...
April 20, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28432466/calpain-inhibition-prevents-flotillin-re-ordering-and-src-family-activation-during-capacitation
#10
Deneb Maldonado-García, Monica L Salgado-Lucio, Ana L Roa-Espitia, Tania Reyes-Miguel, Enrique O Hernández-González
Prior to fertilization, mammalian sperm undergo several molecular, biochemical and physiological changes in a process termed capacitation. However, the mechanisms explaining the involvement of cytoskeletal remodeling and membrane re-ordering in each process prior to fertilization remain poorly understood. We found that the migration of both flotillin microdomains and Src family kinases towards the apical ridge of guinea pig sperm occurs under capacitating conditions. This re-ordering is associated with spectrin cleavage by calpain...
April 22, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28428115/p300-and-c-ebp%C3%AE-regulated-ikk%C3%AE-expression-are-involved-in-thrombin-induced-il-8-cxcl8-expression-in-human-lung-epithelial-cells
#11
Zheng-Wei Huang, Gi-Shih Lien, Chien-Huang Lin, Chun-Ping Jiang, Bing-Chang Chen
Asthma and chronic obstructive pulmonary disease (COPD) are common chronic lung inflammatory diseases. Thrombin and interleukin (IL)-8/C-X-C chemokine ligand 8 (CXCL8) play critical roles in lung inflammation. Our previous study showed that c-Src-dependent IκB kinase (IKK)/IκBα/nuclear factor (NF)-κB and mitogen-activated protein kinase kinase kinase 1 (MEKK1)/extracellular signal-regulated kinase (ERK)/ribosomal S6 protein kinase (RSK)-dependent CAAT/enhancer-binding protein β (C/EBPβ) activation are involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells...
April 17, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28428058/the-pseudomonas-aeruginosa-lectin-leca-triggers-host-cell-signalling-by-glycosphingolipid-dependent-phosphorylation-of-the-adaptor-protein-crkii
#12
Shuangshuang Zheng, Thorsten Eierhoff, Sahaja Aigal, Annette Brandel, Roland Thuenauer, Sophie de Bentzmann, Anne Imberty, Winfried Römer
The human pathogen Pseudomonas aeruginosa induces phosphorylation of the adaptor protein CrkII by activating the non-receptor tyrosine kinase Abl to promote its uptake into host cells. So far, specific factors of P. aeruginosa, which induce Abl/CrkII signalling, are entirely unknown. In this research, we employed human lung epithelial cells H1299, Chinese hamster ovary cells and P. aeruginosa wild type strain PAO1 to study the invasion process of P. aeruginosa into host cells by using microbiological, biochemical and cell biological approaches such as Western Blot, immunofluorescence microscopy and flow cytometry...
April 17, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28427224/ponatinib-promotes-a-g1-cell-cycle-arrest-of-merlin-nf2-deficient-human-schwann-cells
#13
Alejandra M Petrilli, Jeanine Garcia, Marga Bott, Stephani Klingeman Plati, Christine T Dinh, Olena R Bracho, Denise Yan, Bing Zou, Rahul Mittal, Fred F Telischi, Xue-Zhong Liu, Long-Sheng Chang, D Bradley Welling, Alicja J Copik, Cristina Fernández-Valle
Neurofibromatosis type 2 (NF2) is a genetic syndrome that predisposes individuals to multiple benign tumors of the central and peripheral nervous systems, including vestibular schwannomas. Currently, there are no FDA approved drug therapies for NF2. Loss of function of merlin encoded by the NF2 tumor suppressor gene leads to activation of multiple mitogenic signaling cascades, including platelet-derived growth factor receptor (PDGFR) and SRC in Schwann cells. The goal of this study was to determine whether ponatinib, an FDA-approved ABL/SRC inhibitor, reduced proliferation and/or survival of merlin-deficient human Schwann cells (HSC)...
March 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427180/mmp-11-promoted-the-oral-cancer-migration-and-fak-src-activation
#14
Chung-Han Hsin, Ying-Erh Chou, Shun-Fa Yang, Shih-Chi Su, Yi-Ting Chuang, Shu-Hui Lin, Chiao-Wen Lin
Matrix metalloproteinase-11 (MMP-11) has been observed in most invasive human carcinomas. The current study investigated the association between the clinicopathological characteristics and MMP-11 expression in oral squamous cell carcinoma (OSCC) patients. Immunohistochemistry (IHC) staining was performed to assess MMP-11 expression in 279 patients with OSCC. In addition, the metastatic effects of the MMP-11 overexpression on the OSCC cells were also investigated. We found that MMP-11 expression was present in 118/279 (42...
March 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#15
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28424251/nuclear-shp2-directs-normal-embryo-implantation-via-facilitating-the-er%C3%AE-tyrosine-phosphorylation-by-the-src-kinase
#16
Hao Ran, Shuangbo Kong, Shuang Zhang, Jianghong Cheng, Chan Zhou, Bo He, Qiliang Xin, John P Lydon, Francesco J DeMayo, Gen-Sheng Feng, Guoliang Xia, Zhongxian Lu, Chao Wang, Haibin Wang
Estrogen and progesterone coupled with locally produced signaling molecules are essential for embryo implantation. However, the hierarchical landscape of the molecular pathways that governs this process remains largely unexplored. Here we show that the protein tyrosine phosphatase Shp2, a positive transducer of RTK signaling, is predominately localized in the nuclei in the periimplantation mouse uterus. Uterine-specific deletion of Shp2 exhibits reduced progesterone receptor (PR) expression and progesterone resistance, which derails normal uterine receptivity, leading to complete implantation failure in mice...
April 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28423620/exosomal-mir-940-maintains-src-mediated-oncogenic-activity-in-cancer-cells-a-possible-role-for-exosomal-disposal-of-tumor-suppressor-mirnas
#17
Mohammed H Rashed, Pinar Kanlikilicer, Cristian Rodriguez-Aguayo, Martin Pichler, Recep Bayraktar, Emine Bayraktar, Cristina Ivan, Justyna Filant, Andreia Silva, Burcu Aslan, Merve Denizli, Rahul Mitra, Bulent Ozpolat, George A Calin, Anil K Sood, Mohamed F Abd-Ellah, Gouda K Helal, Gabriel Lopez Berestein
Exosomes have emerged as important mediators of diverse biological functions including tumor suppression, tumor progression, invasion, immune escape and cell-to-cell communication, through the release of molecules such as mRNAs, miRNAs, and proteins. Here, we identified differentially expressed exosomal miRNAs between normal epithelial ovarian cell line and both resistant and sensitive ovarian cancer (OC) cell lines. We found miR-940 as abundant in exosomes from SKOV3-IP1, HeyA8, and HeyA8-MDR cells. The high expression of miR-940 is associated with better survival in patients with ovarian serous cystadenocarcinoma...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28420099/na%C3%A2-%C2%BAi-k%C3%A2-%C2%BAi-dependent-and-independent-signaling-triggered-by-cardiotonic-steroids-facts-and-artifacts
#18
REVIEW
Sergei N Orlov, Elizaveta A Klimanova, Artem M Tverskoi, Elizaveta A Vladychenskaya, Larisa V Smolyaninova, Olga D Lopina
Na⁺,K⁺-ATPase is the only known receptor of cardiotonic steroids (CTS) whose interaction with catalytic α-subunits leads to inhibition of this enzyme. As predicted, CTS affect numerous cellular functions related to the maintenance of the transmembrane gradient of monovalent cations, such as electrical membrane potential, cell volume, transepithelial movement of salt and osmotically-obliged water, symport of Na⁺ with inorganic phosphate, glucose, amino acids, nucleotides, etc. During the last two decades, it was shown that side-by-side with these canonical Na⁺i/K⁺i-dependent cellular responses, long-term exposure to CTS affects transcription, translation, tight junction, cell adhesion and exhibits tissue-specific impact on cell survival and death...
April 14, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28419476/cortactin-a-lyn-substrate-is-a-checkpoint-molecule-at-the-intersection-of-bcr-and-cxcr4-signalling-pathway-in-chronic-lymphocytic-leukaemia-cells
#19
Veronica Martini, Cristina Gattazzo, Federica Frezzato, Valentina Trimarco, Marco Pizzi, Giorgia Chiodin, Filippo Severin, Edoardo Scomazzon, Vincenza Guzzardo, Deborah Saraggi, Flavia Raggi, Leonardo Martinello, Monica Facco, Andrea Visentin, Francesco Piazza, Anna Maria Brunati, Gianpietro Semenzato, Livio Trentin
Cortactin (CTTN) is a substrate of the Src kinase Lyn that is known to play an actin cytoskeletal regulatory role involved in cell migration and cancer progression following its phosphorylation at Y421. We recently demonstrated that Cortactin is overexpressed in patients with chronic lymphocytic leukaemia (CLL). This work was aimed at defining the functional role of Cortactin in these patients. We found that Cortactin is variably expressed in CLL patients both in the peripheral blood and lymph nodes and that its expression correlates with the release of matrix metalloproteinase 9 (MMP-9) and the motility of neoplastic cells...
April 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28418351/-connexin-43-expression-in-human-brain-glial-tumors
#20
E Yu Kirichenko, A F Savchenko, D V Kozachenko, M A Akimenko, S Yu Filippova, A E Matsionis, P E Povilaitite
AIM: Тo conduct an immunohistochemical (IHC) study of the expression of connexin 43 in the samples of glial tumors of various grades: gemistocytic astrocytomas (Grade 2), oligodendrogliomas (Grade 2) and glioblastomas (Grade 4). MATERIAL AND METHODS: The material investigated was fragments of human brain glial tumors (grade 2 gemistocytic astrocytomas (n=2), grade 2 oligodendrogliomas (n=2), and grade 4 glioblastomas (n=14) and those of tumor-surrounding tissue (n=4)...
2017: Arkhiv Patologii
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