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https://www.readbyqxmd.com/read/29045015/the-small-molecule-mertk-inhibitor-unc2025-decreases-platelet-activation-and-prevents-thrombosis
#1
Brian R Branchford, Timothy J Stalker, Luke Law, Gilbert Acevedo, Susan Sather, Christine Brzezinski, Katina M Wilson, Katherine Minson, Alisa B Lee-Sherick, Pavel Davizon-Castillo, Christopher Ng, Weihe Zhang, Keith B Neeves, Steven R Lentz, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Deborah DeRyckere, Lawrence F Brass, Douglas K Graham, Jorge A Di Paola
BACKGROUND: Gas6 signals through the TAM (TYRO-3, AXL, MERTK) receptor family mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb β3 integrin. OBJECTIVE: Here we describe anti-thrombotic effects mediated by UNC2025, a small molecule MERTK tyrosine kinase inhibitor. METHODS: MERTK phosphorylation and downstream signaling were assessed by immunoblot. Light transmission aggregometry, flow cytometry, and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregate formation in vitro...
October 17, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29044966/v1b-vasopressin-receptor-trafficking-and-signaling%C3%A2-role-of-arrestins-g-proteins-and-src-kinase
#2
Sanja Perkovska, Catherine Méjean, Mohammed Akli Ayoub, Juan Li, Floriane Hemery, Maithé Corbani, Nadine Laguette, Maria-Angeles Ventura, Hélène Orcel, Thierry Durroux, Bernard Mouillac, Christiane Mendre
The signaling pathway of G protein-coupled receptors (GPCRs) is strongly linked to their trafficking profile. Little is known about the molecular mechanisms involved in the vasopressin receptor V1b subtype (V1b R) trafficking and its impact on receptor signaling and regulation. For this purpose, we investigated the role of β-arrestins in receptor desensitization, internalization and recycling and attempted to dissect the V1b R-mediated MAP Kinase pathway. Using β-arrestin 1-2 KO-MEF cells, we demonstrated that both β-arrestin 1 and 2 play a fundamental role in internalization and recycling of V1b R with a rapid and transient V1b R-β-arrestin interaction in contrast to a slow and long-lasting β-arrestin recruitment of the V2 vasopressin receptor subtype (V2 R)...
October 16, 2017: Traffic
https://www.readbyqxmd.com/read/29042082/the-proto-oncogene-tyrosine-protein-kinase-src-is-essential-for-macrophage-myofibroblast-transition-during-renal-scarring
#3
Patrick Ming-Kuen Tang, Shuang Zhou, Chun-Jie Li, Jinyue Liao, Jun Xiao, Qing-Ming Wang, Guang-Yu Lian, Jinhong Li, Xiao-Ru Huang, Ka-Fai To, Chi-Fai Ng, Charing Ching-Ning Chong, Ronald Ching-Wa Ma, Tin-Lap Lee, Hui-Yao Lan
Src activation has been associated with fibrogenesis after kidney injury. Macrophage-myofibroblast transition is a newly identified process to generate collagen-producing myofibroblasts locally in the kidney undergoing fibrosis in a TGF-β/Smad3-dependent manner. The potential role of the macrophage-myofibroblast transition in Src-mediated renal fibrosis is unknown. In studying this by RNA sequencing at single-cell resolution, we uncovered a unique Src-centric regulatory gene network as a key underlying mechanism of macrophage-myofibroblast transition...
October 14, 2017: Kidney International
https://www.readbyqxmd.com/read/29040064/strong-impact-on-plasma-protein-profiles-by-precentrifugation-delay-but-not-by-repeated-freeze-thaw-cycles-as-analyzed-using-multiplex-proximity-extension-assays
#4
Qiujin Shen, Johan Björkesten, Joakim Galli, Daniel Ekman, John Broberg, Niklas Nordberg, Annika Tillander, Masood Kamali-Moghaddam, Gunnel Tybring, Ulf Landegren
Background A number of factors regarding blood collection, handling and storage may affect sample quality. The purpose of this study was to assess the impact on plasma protein profiles by delayed centrifugation and plasma separation and multiple freeze-thaw cycles. Methods Blood samples drawn from 16 healthy individuals were collected into ethylenediaminetetraacetic acid tubes and kept either at 4 °C or 22 °C for 1-36 h prior to centrifugation. Plasma samples prepared 1 h after venipuncture were also subjected to two to eight cycles of freezing at -80 °C and thawing at 22 °C...
October 17, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/29040002/fak-src-paxillin-system-expression-and-disease-outcome-in-human-neuroblastoma
#5
Panagiotis Kratimenos, Ioannis Koutroulis, Vasiliki Syriopoulou, Christina Michailidi, Maria Delivoria-Papadopoulos, Jerzy Klijanienko, Stamatios Theocharis
BACKGROUND: Neuroblastoma (NB) often presents with metastatic disease and poor survival. The need for new prognostic markers remains invaluable. The FAK-Src-Paxillin protein system is associated with aggressive phenotype in adult malignancies but is largely unexplored in pediatric NB. OBJECTIVE: To assess FAK-Src-Paxillin protein expression in human NB cell lines and clinical cytology material and to delineate its association with survival. DESIGN/METHODS: Western blot and immunohistochemistry were applied for FAK-Src-Paxillin expression in NB cell lines and 23 human cytology specimens, respectively...
October 17, 2017: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/29038344/blocking-myristoylation-of-src-inhibits-its-kinase-activity-and-suppresses-prostate-cancer-progression
#6
Sungjin Kim, Omar Awad Alsaidan, Octavia Goodwin, Qianjin Li, Essilvo Sulejmani, Zhen Han, Aiping Bai, Thomas Albers, Zanna Beharry, Y George G Zheng, James S Norris, Zdzislaw M Szulc, Alicja Bielawska, Iryna Lebedyeva, Scott D Pegan, Houjian Cai
Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or post-translational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacological evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell cycle progression, proliferation and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion...
October 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/29037860/neurotrophin-receptors-trka-p75-ntr-and-sortilin-are-increased-and-targetable-in-thyroid-cancer
#7
Sam Faulkner, Philip Jobling, Christopher Rowe, Sonia Rodriguez-Oliveira, Severine Roselli, Rick Thorne, Christopher Oldmeadow, John Attia, Chen Chen Jiang, Xu Dong Zhang, Marjorie M Walker, Hubert Hondermarck
Neurotrophin receptors are emerging targets in oncology, but their clinicopathological significance in thyroid cancer is unclear. Here, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75(NTR), and the pro-neurotrophin receptor sortilin were analyzed by immunohistochemistry in a cohort of thyroid cancers (n=128), and compared with adenomas and normal thyroid tissues (n=62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0...
October 13, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/29036202/toxoplasma-gondii-induces-fak-src-stat3-signaling-during-infection-of-host-cells-that-prevents-parasite-targeting-by-autophagy
#8
Jose-Andres C Portillo, Luis Muniz-Feliciano, Yalitza Lopez Corcino, So Jung Lee, Jennifer Van Grol, Sarah J Parsons, William P Schiemman, Carlos S Subauste
Targeting of Toxoplasma gondii by autophagy is an effective mechanism by which host cells kill the protozoan. Thus, the parasite must avoid autophagic targeting to survive. Here we show that the mammalian cytoplasmic molecule Focal Adhesion Kinase (FAK) becomes activated during invasion of host cells. Activated FAK appears to accompany the formation of the moving junction (as assessed by expression the parasite protein RON4). FAK activation was inhibited by approaches that impaired β1 and β3 integrin signaling...
October 16, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29035389/-mcc-protein-interacts-with-e-cadherin-and-%C3%AE-catenin-strengthening-cell-cell-adhesion-of-hct116-colon-cancer-cells
#9
F A Benthani, D Herrmann, P N Tran, L Pangon, M C Lucas, A H Allam, N Currey, S Al-Sohaily, M Giry-Laterriere, J Warusavitarne, P Timpson, M R J Kohonen-Corish
E-cadherin and β-catenin are key proteins that are essential in the formation of the epithelial cell layer in the colon but their regulatory pathways that are disrupted in cancer metastasis are not completely understood. Mutated in colorectal cancer (MCC) is a tumour suppressor gene that is silenced by promoter methylation in colorectal cancer and particularly in patients with increased lymph node metastasis. Here, we show that MCC methylation is found in 45% of colon and 24% of rectal cancers and is associated with proximal colon, poorly differentiated, circumferential and mucinous tumours as well as increasing T stage and larger tumour size...
October 16, 2017: Oncogene
https://www.readbyqxmd.com/read/29035365/omega-3-fatty-acid-epoxides-are-autocrine-mediators-that-control-the-magnitude-of-ige-mediated-mast-cell-activation
#10
Yuta Shimanaka, Nozomu Kono, Yoshitaka Taketomi, Makoto Arita, Yoshimichi Okayama, Yuki Tanaka, Yasumasa Nishito, Tatsuki Mochizuki, Hiroyuki Kusuhara, Alexander Adibekian, Benjamin F Cravatt, Makoto Murakami, Hiroyuki Arai
Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate-derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell-derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcɛRI cross-linking...
October 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29034995/mir-1-suppresses-the-proliferation-and-promotes-the-apoptosis-of-esophageal-carcinoma-cells-by-targeting-src
#11
Zhicong Liao, Xiaojun Wang, Hongwei Liang, Ao Yu, Uzair Ur Rehman, Qian Fan, Yue Hu, Chen Wang, Zhen Zhou, Tao Wang
Nonreceptor tyrosine kinase c-Src, also known as Src, is a potent oncogene involved in a series of biological processes including cell growth, differentiation, and apoptosis; however, its expression pattern and function in esophageal cancer is poorly addressed. In this study, abnormal overexpression of Src protein was observed in esophageal cancer tissues, which fuelled the speculation that microRNA-mediated posttranscriptional regulatory mechanism might be involved. Bioinformatic analyses were applied to identify miRNAs that could potentially target Src...
October 16, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29033837/dioscin-inhibits-hsc-t6-cell-migration-via-adjusting-sdc-4-expression-insights-from-itraq-based-quantitative-proteomics
#12
Lianhong Yin, Yan Qi, Youwei Xu, Lina Xu, Xu Han, Xufeng Tao, Shasha Song, Jinyong Peng
Hepatic stellate cells (HSCs) migration, an important bioprocess, contributes to the development of liver fibrosis. Our previous studies have found the potent activity of dioscin against liver fibrosis by inhibiting HSCs proliferation, triggering the senescence and inducing apoptosis of activated HSCs, but the molecular mechanisms associated with cell migration were not clarified. In this work, iTRAQ (isobaric tags for relative and absolution quantitation)-based quantitative proteomics study was carried out, and a total of 1566 differentially expressed proteins with fold change ≥2...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29032615/regulation-of-the-prometastatic-neuregulin-mmp13-axis-by-src-family-kinases-therapeutic-implications
#13
Ana Orive-Ramos, Samuel Seoane, Alberto Ocaña, Atanasio Pandiella, Juan Carlos Montero
Metastatic dissemination of tumor cells is responsible for the fatal outcome of breast cancer. Therefore, understanding the mechanisms involved in dissemination is essential for the development of new therapeutic strategies to prevent metastasis. One mechanism involved in metastatic dissemination of breast cancer cells is dependent on control of the production of matrix metalloproteinases by the neuregulins (NRGs). The NRGs are polypeptide factors that act by binding to the ErbB/HER subfamily of receptor tyrosine kinases...
October 15, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29032182/catalpol-suppresses-osteosarcoma-cell-proliferation-through-blocking-epithelial-mesenchymal-transition-emt-and-inducing-apoptosis
#14
Lei Wang, Gui-Bin Xue
Catalpol, an iridoid glucoside compound, is reported to possess diverse pharmacological actions. However, its effects on osteosarcoma are little to be known. In the present study, we showed that catalpol could strongly suppress osteosarcoma progression. Catalpol dose-dependently reduced the cancer cell viability. The migration of osteosarcoma cells was also consistently suppressed by catalpol treatment using the wound healing and transwell migration analysis. Catalpol reduced the expressions of Kras, receptor for activated C-kinase 1(RACK1) and matrix metalloproteinase (MMP)-2 in a dose-dependent manner, revealing the blockage of migration...
October 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29031599/interaction-of-dj-1-with-lyn-is-essential-for-ige-mediated-stimulation-of-human-mast-cells
#15
Do-Kyun Kim, Michael A Beaven, Dean D Metcalfe, Ana Olivera
BACKGROUND: DJ-1 is a redox-sensitive protein with multiple roles in cell homeostasis whose levels are altered in mast cell (MC)-related disorders. However, whether DJ-1 can regulate human MC function is unknown. OBJECTIVE: We sought to investigate the potential role of DJ-1 in the responses of human MCs to antigen stimulation. METHODS: DJ-1 was silenced in human CD34(+)-derived and LAD2 MCs using lentiviral sh-RNA constructs. Release of β-hexosaminidase, PGD2 and GM-CSF and changes in reactive oxygen species (ROS) levels were measured after FcεRI engagement...
October 12, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29026317/high-expression-of-sam68-in-sacral-chordomas-is-associated-with-worse-clinical-outcomes
#16
Hai Wen, Pengzhi Li, Hong Ma, Jiaoyun Zheng, Yipin Yu, Guohua Lv
Src-associated in mitosis of 68 kDa (Sam68), also known as KHDRBS1 (KH domain-containing, RNA-binding, signal transduction-associated 1), is a member of the signal transduction and activation of RNA family. Previous studies have demonstrated that the aberrant expression of Sam68 is associated with the progression and prognosis of a variety of cancers, but little is known about its expression and role in chordomas, which are rare and aggressive bone neoplasms. In this study, we analyzed 40 tumor tissues and 20 distant normal tissues obtained from 40 patients with sacral chordoma using immunohistochemistry, and observed the expression of Sam68 was significantly upregulated in sacral chordomas compared with normal tissues (P=0...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29025973/dynamic-multi-site-phosphorylation-by-fyn-and-abl-drives-the-interaction-between-crkl-and-the-novel-scaffolding-receptors-dcbld1-and-dcbld2
#17
Anna M Schmoker, Jaye L Weinert, Kyle J Kellett, Hannah E Johnson, Ryan M Joy, Marion E Weir, Alicia M Ebert, Bryan A Ballif
Discoidin, CUB, and LCCL Domain-containing (DCBLD) 2 is a neuropilin-like transmembrane scaffolding receptor with known and anticipated roles in vascular remodeling and neuronal positioning. DCBLD2 is also upregulated in several cancers and can drive glioblastomas downstream of activated Epidermal Growth Factor Receptor. While a few studies have shown either a positive or negative role for DCBLD2 in regulating growth factor receptor signaling, little is known about the conserved signaling features of DCBLD family members that drive their molecular activities...
October 12, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29025591/identification-of-a-novel-csf3r-sptan1-fusion-gene-in-an-atypical-chronic-myeloid-leukemia-patient-with-t-1-9-p34-q34-by-rna-seq
#18
Guangying Sheng, Jian Zhang, Zhao Zeng, Jinlan Pan, Qinrong Wang, Lijun Wen, Yang Xu, Depei Wu, Suning Chen
Membrane-proximal and truncated mutations of colony-stimulating factor 3 receptor (CSF3R) are frequently found in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). However, rearrangement involving CSF3R in hematological neoplasms has not been reported. Here, we report a case of a 21-year-old female diagnosed as aCML with t(1;9)(p34;q34) who presented a CSF3R rearrangement. First, RNA sequencing identified a novel fusion transcript involving exon 17 of CSF3R and exon 50 of non-erythrocytic-1-spectrin-alpha (SPTAN1)...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/29025042/stage-specific-follicular-extracellular-vesicle-uptake-and-regulation-of-bovine-granulosa-cell-proliferation
#19
Wei-Ting Hung, Raphatphorn Navakanitworakul, Tarique Khan, Pan Zhang John S Davis, Lynda K McGinnis, Lane K Christenson
Follicular fluid within ovarian antral follicles contains numerous factors, which influence the development of a healthy oocyte including nucleic acids, steroids, proteins, and extracellular vesicles (EVs). Current evidence indicates that follicular EVs promote changes in cellular gene expression and support cumulus-oocyte-complex expansion in vitro. In this study, we found EVs from different sized follicles differentially stimulate granulosa cell proliferation and this could be explained by both the differential contents associated, on or within the vesicles and by the preferential uptake of EVs dependent on follicle size from which they were isolated...
August 28, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/29024930/effect-of-concurrent-src-kinase-inhibition-with-short-duration-hypothermia-on-ca2-calmodulin-kinase-iv-activity-and-neuropathology-after-hypoxia-ischemia-in-the-newborn-swine-brain
#20
Panagiotis Kratimenos, Ioannis Koutroulis, Amit Jain, Shadi Malaeb, Maria Delivoria-Papadopoulos
BACKGROUND: Hypoxia-ischemia (HI) results in increased activation of Ca2+/calmodulin kinase IV (CaM kinase IV) mediated by Src kinase. Therapeutic hypothermia ameliorates neuronal injury in the newborn. HYPOTHESIS: Inhibition of Src kinase concurrently with hypothermia further attenuates the hypoxia-induced increased activation of CaM kinase IV compared with hypothermia alone. DESIGN/METHODS: Ventilated piglets were exposed to HI, received saline or a selective Src kinase inhibitor (PP2), and were cooled to 33°C...
October 13, 2017: Neonatology
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