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https://www.readbyqxmd.com/read/28638122/synergistic-effects-of-various-her-inhibitors-in-combination-with-igf-1r-c-met-and-src-targeting-agents-in-breast-cancer-cell-lines
#1
Aryan Stanley, G Hossein Ashrafi, Alan M Seddon, Helmout Modjtahedi
Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28637841/protein-tyrosine-phosphatase-%C3%AE-mediates-the-sema3a-induced-cortical-basal-dendritic-arborization-through-the-activation-of-fyn-tyrosine-kinase
#2
Fumio Nakamura, Takako Okada, Maria Shishikura, Noriko Uetani, Masahiko Taniguchi, Takeshi Yagi, Yoichiro Iwakura, Toshio Ohshima, Yoshio Goshima, Stephen M Strittmatter
Leukocyte common antigen related (LAR) class protein tyrosine phosphatases (PTPs) are critical for axonal guidance; however, their relation to specific guidance cues is poorly defined. We here show that PTP-3, LAR homologue in C. elegans, is involved in axon guidance regulated by Sema2A-signaling. PTPδ, one of vertebrate LAR class PTPs, participates in Sema3A-induced growth cone collapse response of primary cultured dorsal root ganglion neurons from M. musculus embryos. In vivo, however, the contribution of PTPδ in Sema3A-regualted axon guidance was minimal...
June 21, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28637715/tyrosine-kinase-inhibitors-protect-the-salivary-gland-from-radiation-damage-by-inhibiting-activation-of-protein-kinase-c-%C3%AE
#3
Sten M Wie, Elizabeth Wellberg, Sana D Karam, Mary E Reyland
In patients undergoing irradiation therapy, injury to non-tumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined Protein Kinase C-delta (PKCδ) as a regulator of DNA damage induced apoptosis and have shown that phosphorylation of PKCδ by c-Abl and c-Src activates its pro-apoptotic function.  Here we have explored the use of tyrosine kinase inhibitors (TKIs) of c-Src and c-Abl to block activation of PKCδ for radioprotection of the salivary gland.  Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKCδ and inhibited IR-induced apoptosis in vitro  To determine if TKIs can provide radioprotection of salivary gland function in vivo, mice were treated with TKIs and a single or fractionated doses of irradiation...
June 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28637676/editorial-focus-on-balance-between-s-nitrosylation-and-denitrosylation-modulates-myoblast-proliferation-independently-of-soluble-guanylyl-cyclase-activation
#4
Hugo P Monteiro, Fernando T Ogata
Myogenesis involves a complex series of signaling events that will result in the formation of muscle fibers. The participation of nitric oxide (NO) in myogenesis is well established. NO generation in skeletal muscle comes from the neuronal isoform of the NO synthase (nNOS). NO signals through cGMP production and s-nitrosylation of proteins in skeletal muscle. In skeletal muscle, nNOS interacts with two domains of caveolin-3 which is part of caveolae, and forms a signaling complex through additional interactions with Src kinase and p21Ras...
June 21, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28636830/attenuation-of-hepatic-steatosis-by-purple-sweet-potato-color-is-associated-with-blocking-src-erk-c-ebp%C3%AE-signalling-in-high-fat-diet-treated-mice
#5
Xin Wang, Zi-Feng Zhang, Gui-Hong Zheng, Ai-Min Wang, Chun-Hui Sun, Su-Ping Qin, Juan Zhuang, Jun Lu, Dai-Fu Ma, Yuan-Lin Zheng
Our previous work showed that purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, effectively improved hepatic glucose metabolic dysfunction in high-fat diet (HFD)-treated mice. This study investigated the effects of PSPC on HFD-induced hepatic steatosis and the signalling events associated with these effects. Mice were divided into four groups: Control group, HFD group, HFD+PSPC group and PSPC group. PSPC was administered daily for 20 weeks at oral doses of 700 mg/kg/day. Our results showed that PSPC significantly improved obesity and related metabolic parameters, as well as liver injury in HFD-treated mice...
June 21, 2017: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
https://www.readbyqxmd.com/read/28634209/genetic-evidence-that-%C3%AE-arrestins-are-dispensable-for-the-initiation-of-%C3%AE-2-adrenergic-receptor-signaling-to-erk
#6
Morgan O'Hayre, Kelsie Eichel, Silvia Avino, Xuefeng Zhao, Dana J Steffen, Xiaodong Feng, Kouki Kawakami, Junken Aoki, Karen Messer, Roger Sunahara, Asuka Inoue, Mark von Zastrow, J Silvio Gutkind
The β2-adrenergic receptor (β2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in β2AR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for β2AR internalization...
June 20, 2017: Science Signaling
https://www.readbyqxmd.com/read/28634059/a-pumpkin-polysaccharide-induces-apoptosis-by-inhibiting-the-jak2-stat3-pathway-in-human-hepatoma-hepg2-cells
#7
Weixi Shen, Chunhong Chen, Yuanyuan Guan, Xiaowei Song, Yinghua Jin, Jingfang Wang, Yu Hu, Tao Xin, Qiuying Jiang, Li Zhong
The purpose of this study is to investigate the effect of a purified polysaccharide (PPPF) from pumpkin fruit on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. The results showed that PPPF or STAT3 siRNA inhibits the cell growth of HepG2 cells via induction of apoptosis. Moreover, PPPF is able to suppress both constitutive and IL-6-induced phosphorylation of STAT3 (on Tyr705) and subsequent nuclear translocation in cancer cells. Such inhibition is found to be achieved through down-regulation of constitutive phosphorylation of JAK2, but not JAk1, c-Src, ERK1/2, and Akt, which means STAT3 tyrosine phosphorylation in HepG2 cells following PPPF treatment is associated with a reduction in JAK2 activity...
June 17, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28629162/promotion-of-tumor-invasion-by-tumor-associated-macrophages-the-role-of-csf-1-activated-phosphatidylinositol-3-kinase-and-src-family-kinase-motility-signaling
#8
REVIEW
Amy R Dwyer, Eloise L Greenland, Fiona J Pixley
Macrophages interact with cells in every organ to facilitate tissue development, function and repair. However, the close interaction between macrophages and parenchymal cells can be subverted in disease, particularly cancer. Motility is an essential capacity for macrophages to be able to carry out their various roles. In cancers, the macrophage's interstitial migratory ability is frequently co-opted by tumor cells to enable escape from the primary tumor and metastatic spread. Macrophage accumulation within and movement through a tumor is often stimulated by tumor cell production of the mononuclear phagocytic growth factor, colony-stimulating factor-1 (CSF-1)...
June 18, 2017: Cancers
https://www.readbyqxmd.com/read/28627476/deciphering-the-protein-protein-interaction-network-regulating-hepatocellular-carcinoma-metastasis
#9
Guoxuan Qin, Mengjiao Dang, Huajun Gao, Hao Wang, Fengting Luo, Ruibing Chen
Hepatocellular carcinoma (HCC) is one of the leading causes of mortality related to cancer all over the world. To better understand the molecular mechanisms of HCC metastasis, we analyzed the proteome of three HCC cell lines with different metastasis potentials by quantitative proteomics and bioinformatics analysis. As a result, we identified 378 cellular proteins potentially associated to HCC metastasis, and constructed a highly connected protein-protein interaction (PPI) network. Functional annotation of the network uncovered prominent pathways and key roles of these proteins, suggesting that the metabolism and cytoskeleton biological processes are greatly involved with HCC metastasis...
June 13, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28626446/gnrh-induces-erk-dependent-bleb-formation-in-gonadotrope-cells-involving-recruitment-of-members-of-a-gnrh-receptor-associated-signalosome-to-the-blebs
#10
Liat Rahamim-Ben Navi, Anna Tsukerman, Alona Feldman, Philippa Melamed, Melanija Tomić, Stanko S Stojilkovic, Ulrich Boehm, Rony Seger, Zvi Naor
We have previously described a signaling complex (signalosome) associated with the GnRH receptor (GnRHR). We now report that GnRH induces bleb formation in the gonadotrope-derived LβT2 cells. The blebs appear within ~2 min at a turnover rate of ~2-3 blebs/min and last for at least 90 min. Formation of the blebs requires active ERK1/2 and RhoA-ROCK but not active c-Src. Although the following ligands stimulate ERK1/2 in LβT2 cells: EGF > GnRH > PMA > cyclic adenosine monophosphate (cAMP), they produced little or no effect on bleb formation as compared to the robust effect of GnRH (GnRH > PMA > cAMP > EGF), indicating that ERK1/2 is required but not sufficient for bleb formation possibly due to compartmentalization...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28626342/effects-of-src-kinase-inhibition-on-expression-of-protein-tyrosine-phosphatase-1b-after-brain-hypoxia-in-a-piglet-animal-model
#11
Dimitrios Angelis, Maria Delivoria-Papadopoulos
BACKGROUND: Protein tyrosine phosphatases (PTPs) in conjunction with protein tyrosine kinases (PTKs) regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B) is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28625738/mechanisms-of-paradoxical-activation-of-ampk-by-the-kinase-inhibitors-su6656-and-sorafenib
#12
Fiona A Ross, Simon A Hawley, F Romana Auciello, Graeme J Gowans, Abdelmadjid Atrih, Douglas J Lamont, D Grahame Hardie
SU6656, a Src kinase inhibitor, was reported to increase fat oxidation and reduce body weight in mice, with proposed mechanisms involving AMP-activated protein kinase (AMPK) activation via inhibition of phosphorylation of either LKB1 or AMPK by the Src kinase, Fyn. However, we report that AMPK activation by SU6656 is independent of Src kinases or tyrosine phosphorylation of LKB1 or AMPK and is not due to decreased cellular energy status or binding at the ADaM site on AMPK. SU6656 is a potent AMPK inhibitor, yet binding at the catalytic site paradoxically promotes phosphorylation of Thr172 by LKB1...
June 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28624460/identification-of-kx2-391-as-an-inhibitor-of-hbv-transcription-by-a-recombinant-hbv-based-screening-assay
#13
Keisuke Harada, Hironori Nishitsuji, Saneyuki Ujino, Kunitada Shimotohno
Antiviral therapies for chronic hepatitis B virus (HBV) infection that are currently applicable for clinical use are limited to nucleos(t)ide analogs targeting HBV polymerase activity and pegylated interferon alpha (PEG-IFN). Towards establishing an effective therapy for HBV related diseases, it is important to develop a new anti-HBV agent that suppresses and eradicates HBV. This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection...
June 15, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28619847/targeted-activation-of-the-shp-1-pp2a-signalling-axis-elicits-apoptosis-of-chronic-lymphocytic-leukemia-cells
#14
Elena Tibaldi, Mario Angelo Pagano, Federica Frezzato, Valentina Trimarco, Monica Facco, Giuseppe Zagotto, Giovanni Ribaudo, Valeria Pavan, Luciana Bordin, Andrea Visentin, Francesca Zonta, Gianpietro Semenzato, Anna Maria Brunati, Livio Trentin
The Src Family Kinase (SFK) Lyn is a key factor in the dysregulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is the spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and the serine/threonine phosphatase 2A, eventually triggering apoptosis...
June 15, 2017: Haematologica
https://www.readbyqxmd.com/read/28619275/differentiation-affects-the-release-of-exosomes-from-colon-cancer-cells-and-their-ability-to-modulate-the-behavior-of-recipient-cells
#15
Donatella Lucchetti, Federica Calapà, Valentina Palmieri, Caterina Fanali, Federica Carbone, Alfredo Papa, Ruggero De Maria, Marco De Spirito, Alessandro Sgambato
Exosomes are involved in intercellular communication. We previously reported that sodium butyrate-induced differentiation of HT29 colon cancer cells is associated with a reduced CD133 expression. Herein, we analyzed the role of exosomes in the differentiation of HT29 cells. Exosomes were prepared using ultracentrifugation. Gene expression levels were evaluated by real-time PCR. The cell proliferation rate was assessed by MTT assay and with the electric cell-substrate impedance sensing system, whereas cell motility was assessed using the scratch test and confocal microscopy...
July 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28618271/lck-hck-fgr-mediated-tyrosine-phosphorylation-negatively-regulates-tbk1-to-restrain-innate-antiviral-responses
#16
Shengduo Liu, Shasha Chen, Xinran Li, Shiying Wu, Qian Zhang, Qiuheng Jin, Lin Hu, Ruyuan Zhou, Zhengyang Yu, Fansen Meng, Siwen Wang, Yaowei Huang, Sheng Ye, Li Shen, Zongping Xia, Jian Zou, Xin-Hua Feng, Pinglong Xu
Cytosolic nucleic acid sensing elicits interferon production for primary antiviral defense through cascades controlled by protein ubiquitination and Ser/Thr phosphorylation. Here we show that TBK1, a core kinase of antiviral pathways, is inhibited by tyrosine phosphorylation. The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. Accordingly, antiviral sensing and resistance were substantially enhanced in Lck/Hck/Fgr triple knockout cells and ectopic expression of Lck/Hck/Fgr dampened the antiviral defense in cells and zebrafish...
June 14, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28618084/ccl20-promotes-migration-and-invasiveness-of-human-cancerous-breast-epithelial-cells-in-primary-culture
#17
Antonella Muscella, Carla Vetrugno, Santo Marsigliante
The relation between the tumor and its microenvironment is one of the most interesting and less understood issues. Recently, we showed a role of CCL20 chemokine in proning the healthy tissue neighbouring the tumor to carcinogenesis. Besides, tumor-secreted CCL20 induced proliferation, migration and EMT of healthy cells. In this context, we have studied here if CCL20 had effects on the migration of cancer cells and the intracellular pathways used in breast epithelial cells in primary culture. Using molecular (siRNA) and pharmacological (inhibitors) techniques, we found multiple signaling kinases to be activated and involved in CCL20-induced tumor breast cell migration...
June 15, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28615246/src-family-kinases-in-chronic-kidney-disease
#18
Jun Wang, Shougang Zhuang
Src family kinases (SFKs) belong to non-receptor protein tyrosine kinases (PTKs) and have been implicated in the regulation of numerous cellular processes, including cell proliferation, differentiation, migration and invasion, angiogenesis. The role and mechanisms of SFKs in tumorgenesis have been extensively investigated and some of SFK inhibitors are currently under clinical trials for tumor treatment. Recent studies have also demonstrated the importance of SFKs in regulating the development of various fibrosis related chronic diseases (e...
June 14, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28615245/the-regulatory-1%C3%AE-subunit-of-protein-kinase-a-modulates-renal-cystogenesis
#19
Hong Ye, Xiaofang Wang, Megan M Constans, Caroline R Sussman, Fouad Chebib, Maria V Irazabal, William F Young, Peter C Harris, Lawrence S Kirschner, Vicente E Torres
The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for Autosomal Dominant Polycystic Kidney Disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways...
June 14, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28607598/the-prognostic-value-of-tyrosine-kinase-src-expression-in-locally-advanced-rectal-cancer
#20
Felix Rühlmann, Manuel Nietert, Thilo Sprenger, Hendrik A Wolff, Kia Homayounfar, Peter Middel, Hanibal Bohnenberger, Tim Beissbarth, B Michael Ghadimi, Torsten Liersch, Lena-Christin Conradi
The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity. For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14...
2017: Journal of Cancer
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