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https://www.readbyqxmd.com/read/28210098/mertk-gene-expression-and-photoreceptor-outer-segment-phagocytosis-by-cultured-rat-bone-marrow-mesenchymal-stem-cells
#1
Rong-Mei Peng, Jing Hong, Ying Jin, Yu-Zhao Sun, Yi-Qian Sun, Pei Zhang
BACKGROUND: Bone marrow mesenchymal stem cells (BM-MSCs) are multipotential stem cells that have been used for a broad spectrum of indications. Several investigations have used BM-MSCs to promote photoreceptor survival and suggested that BM-MSCs are a potential source of cell replacement therapy for some forms of retinal degeneration. PURPOSE: To investigate the expression of the MER proto-oncogene, tyrosine kinase (Mertk), involved in the disruption of RPE phagocytosis and the onset of autosomal recessive retinitis pigmentosa in rat BM-MSCs and to compare phagocytosis of the photoreceptor outer segment (POS) by BM-MSCs and RPE cells in vitro...
2017: Molecular Vision
https://www.readbyqxmd.com/read/28184013/phosphatidylserine-sensing-by-tam-receptors-regulates-akt-dependent-chemoresistance-and-pd-l1-expression
#2
Canan Kasikara, Sushil Kumar, Stanley Kimani, Wen-I Tsou, Ke Geng, Viralkumar Davra, Ganapathy Sriram, Connor Devoe, Khanh-Quynh Nguyen, Anita Antes, Allen Krantz, Grzegorz Rymarczyk, Andrzej Wilczynski, Cyril Empig, Bruce D Freimark, Michael Gray, Kyle Schlunegger, Jeff Hutchins, Sergei V Kotenko, Raymond B Birge
: Tyro3, Axl and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases (RTKs) that bind vitamin K-dependent endogenous ligands, Protein S (ProS) and Growth arrest specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radio-resistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment (TME) that can suppress host anti-tumor immunity...
February 9, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28181551/whole-exome-sequencing-using-ion-proton-system-enables-reliable-genetic-diagnosis-of-inherited-retinal-dystrophies
#3
Marina Riera, Rafael Navarro, Sheila Ruiz-Nogales, Pilar Méndez, Anniken Burés-Jelstrup, Borja Corcóstegui, Esther Pomares
Inherited retinal dystrophies (IRD) comprise a wide group of clinically and genetically complex diseases that progressively affect the retina. Over recent years, the development of next-generation sequencing (NGS) methods has transformed our ability to diagnose heterogeneous diseases. In this work, we have evaluated the implementation of whole exome sequencing (WES) for the molecular diagnosis of IRD. Using Ion Proton(TM) system, we simultaneously analyzed 212 genes that are responsible for more than 25 syndromic and non-syndromic IRD...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28145605/the-tam-receptor-tyro3-regulates-myelination-in-the-central-nervous-system
#4
Rainer Akkermann, Andrea Aprico, Ashwyn A Perera, Helena Bujalka, Alistair E Cole, Junhua Xiao, Judith Field, Trevor J Kilpatrick, Michele D Binder
Myelin is an essential component of the mammalian nervous system, facilitating rapid conduction of electrical impulses by axons, as well as providing trophic support to neurons. Within the central nervous system, the oligodendrocyte is the specialized neural cell responsible for producing myelin by a process that is thought to be regulated by both activity dependent and independent mechanisms but in incompletely understood ways. We have previously identified that the protein Gas6, a ligand for a family of tyrosine kinase receptors known as the TAM (Tyro3, Axl, and Mertk) receptors, directly increases oligodendrocyte induced myelination in vitro...
February 1, 2017: Glia
https://www.readbyqxmd.com/read/28144780/inhibition-of-neutrophil-elastase-contributes-to-attenuation-of-lipopolysaccharide-induced-acute-lung-injury-during-neutropenia-recovery-in-mice
#5
Jong Min Lee, Chang Dong Yeo, Hwa Young Lee, Chin Kook Rhee, In Kyoung Kim, Dong Gun Lee, Sang Haak Lee, Jin Woo Kim
PURPOSE: Patients in whom neutropenia recovery is complicated by pneumonia have an increased risk of acute lung injury (ALI) and detrimental outcomes. The aim of the present study was to investigate whether inhibition of neutrophil elastase (NE) is effective in lipopolysaccharide (LPS)-induced ALI during neutropenia recovery in a murine model, and whether it upregulates the activation of the MerTK signaling pathway. METHODS: Cyclophosphamide was given to mice to induce neutropenia...
January 31, 2017: Journal of Anesthesia
https://www.readbyqxmd.com/read/28127639/increased-mer-and-axl-receptor-tyrosine-kinase-expression-on-glomeruli-in-lupus-nephritis
#6
Shanshan Li, Qianyu Guo, Huaqun Zhu, Zhanguo Li, Yin Su, Bao Dong
Mer and Axl receptor tyrosine kinases (MerTK and AxlTK) play important roles in the clearance of apoptotic cells and the inhibition of inflammatory responses. Previous studies demonstrated that they might participate in glomerular injury in mice model. This study aimed to elucidate the expression of MerTK and AxlTK on glomeruli and analyze their clinical significance in lupus nephritis (LN) patients. Twenty-nine LN and 10 primary nephrotic syndrome (NS) patients were recruited. The expression of MerTK and AxlTK on glomeruli was measured by immunohistochemistry...
January 26, 2017: Clinical Rheumatology
https://www.readbyqxmd.com/read/28118606/protein-s-drives-oral-squamous-cell-carcinoma-tumorigenicity-through-regulation-of-axl
#7
Ghada Abboud-Jarrous, Shivam Priya, Avi Maimon, Stuart Fischman, Mayan Cohen-Elisha, Rakefet Czerninski, Tal Burstyn-Cohen
The TAM family of proto-oncogenic receptor protein tyrosine kinases, comprising of TYRO3, AXL, and MERTK, is implicated in many human cancers. Their activation leads to cancer cell proliferation, enhanced migration, invasion, and drug resistance; however how TAMs are activated in cancers is less understood. We previously showed that Protein S (PROS1) is a ligand of the TAM receptors. Here we identify PROS1 as a mediator of Oral Squamous Cell Carcinoma (OSCC) in proliferation, cell survival and migration. We demonstrate that excess PROS1 induces OSCC proliferation and migration...
January 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28075192/loss-of-monocyte-chemoattractant-protein-1-expression-delays-mammary-tumorigenesis-and-reduces-localized-inflammation-in-the-c3-1-sv40tag-triple-negative-breast-cancer-model
#8
Taryn L Cranford, Kandy T Velázquez, Reilly T Enos, Jackie E Bader, Meredith S Carson, Ioulia Chatzistamou, Mitzi Nagarkatti, E Angela Murphy
Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC...
January 11, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28072762/giving-axl-the-axe-targeting-axl-in-human-malignancy
#9
REVIEW
Carl M Gay, Kavitha Balaji, Lauren Averett Byers
The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers...
February 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28067670/mertk-receptor-cleavage-promotes-plaque-necrosis-and-defective-resolution-in-atherosclerosis
#10
Bishuang Cai, Edward B Thorp, Amanda C Doran, Brian E Sansbury, Mat J A P Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira Tabas
Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution...
February 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28049839/gas6-is-a-key-homeostatic-immunological-regulator-of-host-commensal-interactions-in-the-oral-mucosa
#11
Maria Nassar, Yaara Tabib, Tal Capucha, Gabriel Mizraji, Tsipora Nir, Meirav Pevsner-Fischer, Gili Zilberman-Schapira, Oded Heyman, Gabriel Nussbaum, Herve Bercovier, Asaf Wilensky, Eran Elinav, Tal Burstyn-Cohen, Avi-Hai Hovav
The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3-AXL-MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28035529/hereditary-retinal-dystrophy
#12
Thomas C Hohman
As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations associated with inherited retinal dystrophies were identified, it became possible to create animal models in which individual gene were altered to match the human mutations. The retina of these animals were then characterized to assess whether the mutated genes produced retinal phenotypes characteristic of disease-affected patients. Following the identification of a subpopulation of patients with the affected gene and the development of techniques for the viral gene transduction of retinal cells, it has become possible to deliver a copy of the normal gene into the retinal sites of the mutated genes...
December 30, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28035396/anticancer-effect-of-luteolin-is-mediated-by-downregulation-of-tam-receptor-tyrosine-kinases-but-not-interleukin-8-in-non-small-cell-lung-cancer-cells
#13
Youn Ju Lee, Taeho Lim, Min Su Han, Sun-Hwa Lee, Suk-Hwan Baek, Hong-Yan Nan, Chuhee Lee
TAM receptor tyrosine kinases (RTKs), Tyro3, Axl and MerTK, transduce diverse signals responsible for cell survival, growth, proliferation and anti-apoptosis. In the present study, we demonstrated the effect of luteolin, a flavonoid with antioxidant, anti-inflammatory and anticancer activities, on the expression and activation of TAM RTKs and the association with its cytotoxicity in non-small cell lung cancer (NSCLC) cells. We observed the cytotoxic effect of luteolin in parental A549 and H460 cells as well as in cisplatin-resistant A549/CisR and H460/CisR cells...
February 2017: Oncology Reports
https://www.readbyqxmd.com/read/28034848/regulated-intramembrane-proteolysis-of-the-axl-receptor-kinase-generates-an-intracellular-domain-that-localizes-in-the-nucleus-of-cancer-cells
#14
Yinzhong Lu, Jun Wan, Zhifeng Yang, Xiling Lei, Qi Niu, Lanxin Jiang, Willemijn M Passtoors, Aiping Zang, Patrick C Fraering, Fang Wu
Deregulation of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases (RTKs) has recently been demonstrated to predominately promote survival and chemoresistance of cancer cells. Intramembrane proteolysis mediated by presenilin/γ-secretase is known to regulate the homeostasis of some RTKs. In the present study, we demonstrate that AXL, but not TYRO3 or MERTK, is efficiently and sequentially cleaved by α- and γ-secretases in various types of cancer cell lines. Proteolytic processing of AXL redirected signaling toward a secretase-mediated pathway, away from the classic, well-known, ligand-dependent canonical RTK signaling pathway...
December 29, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28032464/discovery-of-macrocyclic-pyrimidines-as-mertk-specific-inhibitors
#15
Andrew L McIver, Weihe Zhang, Qingyang Liu, Xinpeng Jiang, Michael A Stashko, James Nichols, Michael J Miley, Jacqueline Norris-Drouin, Mischa Machius, Deborah DeRyckere, Edgar Wood, Douglas K Graham, H Shelton Earp, Dmitri Kireev, Stephen V Frye, Xiaodong Wang
Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK...
December 28, 2016: ChemMedChem
https://www.readbyqxmd.com/read/28003382/mek1-2-inhibition-promotes-macrophage-reparative-properties
#16
Matthew E Long, William E Eddy, Ke-Qin Gong, Lara L Lovelace-Macon, Ryan S McMahan, Jean Charron, W Conrad Liles, Anne M Manicone
Macrophages have important functional roles in regulating the timely promotion and resolution of inflammation. Although many of the intracellular signaling pathways involved in the proinflammatory responses of macrophages are well characterized, the components that regulate macrophage reparative properties are less well understood. We identified the MEK1/2 pathway as a key regulator of macrophage reparative properties. Pharmacological inhibition of the MEK1/2 pathway by a MEK1/2 inhibitor (MEKi) significantly increased expression of IL-4/IL-13 (M2)-responsive genes in murine bone marrow-derived and alveolar macrophages...
January 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27994735/design-and-synthesis-of-novel-macrocyclic-mer-tyrosine-kinase-inhibitors
#17
Xiaodong Wang, Jing Liu, Weihe Zhang, Michael A Stashko, James Nichols, Michael J Miley, Jacqueline Norris-Drouin, Zhilong Chen, Mischa Machius, Deborah DeRyckere, Edgar Wood, Douglas K Graham, H Shelton Earp, Dmitri Kireev, Stephen V Frye
Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC50 below 40 nM in a cell-based MerTK phosphor-protein ELISA assay...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27958361/deficiency-of-axl-in-bone-marrow-derived-cells-does-not-affect-advanced-atherosclerotic-lesion-progression
#18
Manikandan Subramanian, Jonathan D Proto, Glenn K Matsushima, Ira Tabas
AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl(-/-) or wild-type mice were transplanted into lethally irradiated Ldlr(-/-) mice...
December 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27916840/ligand-activation-of-tam-family-receptors-implications-for-tumor-biology-and-therapeutic-response
#19
REVIEW
Viralkumar Davra, Stanley G Kimani, David Calianese, Raymond B Birge
The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology...
November 29, 2016: Cancers
https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#20
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently overexpressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL6R; the Notch receptors; type-I and -III TGFβ receptors; receptor tyrosine kinases (RTK) such as HER2, HER4, and VEGFR2; and, in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
February 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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