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Shp1 OR Shp2

Artemis Gogos, Juan Cristobal Jimenez, Jennifer C Chang, Reid V Wilkening, Michael J Federle
The Rgg2/3 quorum sensing (QS) system is conserved among all sequenced isolates of Group A Streptococcus (GAS, Streptococcus pyogenes ). The molecular architecture of the system consists of a transcriptional activator (Rgg2) and a transcriptional repressor (Rgg3) under the control of autoinducing peptide pheromones (SHP2 and SHP3). Activation of the Rgg2/3 pathway leads to increases in biofilm formation and resistance to the bactericidal effects of the host factor, lysozyme. In this work, we show that deletion of a small gene, Spy49_0414c , abolished both phenotypes in response to pheromone signaling...
March 19, 2018: Journal of Bacteriology
Fumihiko Hakuno, Shin-Ichiro Takahashi
Insulin-like growth factors (IGFs) bind specifically to the IGF-I receptor on the cell surface of targeted tissues. Ligand binding to the α subunit of the receptor leads to a conformational change in the β subunit, resulting in the activation of receptor tyrosine kinase activity. Activated receptor phosphorylates several substrates, including insulin receptor substrates (IRSs) and Src-homology collagen (Shc). Phosphotyrosine residues in these substrates are recognized by certain Src homology 2 (SH2) domain containing signaling molecules...
March 13, 2018: Journal of Molecular Endocrinology
(no author information available yet)
Targeting SHP2 suppresses ALK inhibitor resistance caused by tyrosine kinase reactivation.
March 9, 2018: Cancer Discovery
Jacey J Liu, Yanjie Li, Wendy S Chen, Yan Liang, Gaowei Wang, Min Zong, Kota Kaneko, Ruiyun Xu, Michael Karin, Gen-Sheng Feng
BACKGROUND AND AIMS: Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs). Most recent data demonstrated a liver tumor-suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogen or Pten loss. We further investigated the effect of Shp2 deficiency on liver tumorigenesis driven by classical oncoproteins c-Met (receptor for HGF), β-catenin and PIK3CA. METHODS: We performed hydrodynamic tail vein injection of two pairs of plasmids expressing c-Met and ΔN90-β-catenin (MET/CAT), or c-Met and PIK3CAH1047R (MET/PIK), into WT and Shp2hep-/- mice...
March 2, 2018: Journal of Hepatology
Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Katherine X Shaw, Satoshi Yoda, Grainne Kerr, Kristine Yu, Jinsheng Liang, Yichen Cao, Yan Chen, Michael S Lawrence, Adam Langenbucher, Justin F Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice T Shaw, Aaron N Hata, Cyril H Benes, Fang Li, Jeffrey A Engelman
Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited...
March 5, 2018: Nature Medicine
Wen-Yan Jin, Ying Ma, Wei-Ya Li, Hong-Lian Li, Run-Ling Wang
SHP2 is a potential target for the development of novel therapies for SHP2-dependent cancers. In our research, with the aid of the 'Receptor-Ligand Pharmacophore' technique, a 3D-QSAR method was carried out to explore structure activity relationship of SHP2 allosteric inhibitors. Structure-based drug design was employed to optimize SHP099, an efficacious, potent, and selective SHP2 allosteric inhibitor. A novel class of selective SHP2 allosteric inhibitors was discovered by using the powerful 'SBP', 'ADMET' and 'CDOCKER' techniques...
February 8, 2018: Computational Biology and Chemistry
Yao-Chen Wang, De-Wei Wu, Tzu-Chin Wu, Lee Wang, Chih-Yi Chen, Huei Lee
Resistance to tyrosine kinase inhibitors (TKIs) results in tumor relapse and poor prognosis in patients with lung adenocarcinoma. TKI resistance caused by epidermal growth factor receptor (EGFR) mutations at T790M and c-Met amplification occurs through persistent activation of the MEK/ERK and PI3K/AKT signaling pathways. We therefore expected that dual inhibitors of both signaling pathways could overcome TKI resistance in lung adenocarcinoma. Here, dioscin was selected from a product library of Chinese naturally occurring compounds and overcame TKI resistance in EGFR-mutated lung adenocarcinoma cells...
2018: International Journal of Biological Sciences
Simon Schliffke, Sophia Buhs, Sarah Bolz, Helwe Gerull, Lisa von Wenserski, Kristoffer Riecken, Boris Fehse, Peter Nollau, Mascha Binder
No abstract text is available yet for this article.
February 23, 2018: Blood
Yao Liu, Huan Jing, Xiaoxing Kou, Chider Chen, Dawei Liu, Yan Jin, Li Lu, Songtao Shi
Programmed cell death-1 (PD-1) belongs to an inhibitory signaling pathway capable of maintaining central and peripheral immune tolerance. Blockage of PD-1 has been identified as a promising immunotherapeutic approach for cancer and chronic infectious diseases. However, it is unknown whether PD-1 pathway regulates stem cell function. It is generally believed that mesenchymal stem cells (MSCs) produce PD-1 ligand, but fail to express PD-1. In this study, we show that neural crest-derived MSCs from dental pulp (MSC-DP), but not MSCs from bone marrow, expressed PD-1...
February 22, 2018: Cell Death and Differentiation
Stéphanie Dayot, Daniela Speisky, Anne Couvelard, Pierre Bourgoin, Valérie Gratio, Jérôme Cros, Vinciane Rebours, Alain Sauvanet, Pierre Bedossa, Valérie Paradis, Philippe Ruszniewski, Alain Couvineau, Thierry Voisin
Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions. We used PDAC-derived cell lines and fresh tissue slices to study the apoptotic role of hypocretin-1/orexin-A and almorexant in vitro and ex vivo . We analyzed in vivo the hypocretin-1/orexin-A and almorexant effect on tumor growth in mice xenografted with PDAC cell lines expressing, or not, OX1R...
January 23, 2018: Oncotarget
Lisa Deng, Briana M Richine, Elizabeth L Virts, Victoria N Jideonwo-Auman, Rebecca J Chan, Reuben Kapur
PTPN11 gain-of-function mutation is the most common mutation found in patients with juvenile myelomonocytic leukemia and DNMT3A loss occurs in over 20% of acute myeloid leukemia patients. We studied the combined effect of both Ptpn11 gain-of-function mutation (D61Y) and Dnmt3a haploinsufficiency on mouse hematopoiesis, the presence of which has been described in both juvenile myelomonocytic leukemia and acute myeloid leukemia patients. Double mutant mice rapidly become moribund relative to any of the other genotypes, which is associated with enlargement of the spleen and an increase in white blood cell counts...
January 19, 2018: Oncotarget
Rizwan Yousaf, Zubair M Ahmed, Arnaud Pj Giese, Robert J Morell, Ayala Lagziel, Alain Dabdoub, Edward R Wilcox, Sheikh Riazuddin, Thomas B Friedman, Saima Riazuddin
A modifier variant can abrogate risk of a monogenic disorder. DFNM1 is a locus on chromosome 1 encoding a dominant suppressor of human DFNB26 recessive, profound deafness. Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin-homology-domain of GAB1, an essential scaffold in the MET/HGF pathway. A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1-associated deafness. In zebrafish, human METTL13 mRNA harboring the modifier allele rescues the GAB1 associated morphant phenotype...
February 6, 2018: Journal of Clinical Investigation
Rima Chattopadhyay, Arul M Mani, Nikhlesh K Singh, Gadiparthi N Rao
In recent years, various studies have demonstrated a role for endogenously derived specialized proresolving mediators such as resolvins in the resolution of inflammation. In exploring the signaling mechanisms, in the present study we show that Resolvin D1 (RvD1) reduces LPS-induced endothelial cell (EC)-monocyte interactions via blocking H2O2-mediated PP2A inactivation, NFκB activation and ICAM1 and VCAM1 expression. In addition, we found that H2O2-mediated SHP2 inhibition leads to tyrosine phosphorylation and inactivation of PP2A by LPS, which in turn, accounts for increased NFκB activation and ICAM1 and VCAM1 expression facilitating EC-monocyte interactions and all these LPS-mediated responses were reduced by RvD1...
February 2, 2018: Free Radical Biology & Medicine
Zhen Cai, Xiu-Yan Hao, Feng-Xin Liu
OBJECTIVE: MicroRNAs (miRs) have been shown to play critical roles in the pathogenesis of oral squamous cell carcinoma (OSCC), the current study is designed to identify the potential role of miR-186 in OSCC. MATERIALS AND METHODS: Realtime polymerase chain reaction was used to determine miR-186 expression in paired tissue samples (OSCC and adjacent normal tissues) and multiple oral cell lines (normal oral keratinocyte HOK cell and OSCC cell lines). Cell viability, colony formation and flow cytometry assays were used to assess the biological function of miR-186...
January 31, 2018: Archives of Oral Biology
Quanri Zhang, Wook-Bin Lee, Ji-Seon Kang, Lark Kyun Kim, Young-Joon Kim
During mycobacteria infection, anti-inflammatory responses allow the host to avoid tissue damage caused by overactivation of the immune system; however, little is known about the negative modulators that specifically control mycobacteria-induced immune responses. Here we demonstrate that integrin CD11b is a critical negative regulator of mycobacteria cord factor-induced macrophage-inducible C-type lectin (Mincle) signaling. CD11b deficiency resulted in hyperinflammation following mycobacterial infection. Activation of Mincle by mycobacterial components turns on not only the Syk signaling pathway but also CD11b signaling and induces formation of a Mincle-CD11b signaling complex...
February 5, 2018: Experimental & Molecular Medicine
Ighodaro Igbe, Xiao-Fei Shen, Wei Jiao, Zhe Qiang, Teng Deng, Sheng Li, Wan-Li Liu, Han-Wei Liu, Guo-Lin Zhang, Fei Wang
Type I interferons (IFN-α/β) have broad and potent immunoregulatory and antiproliferative activities, which are negatively regulated by Src homology domain 2 containing tyrosine phosphatase-2 (SHP-2). Inhibition of SHP2 by small molecules may be a new strategy to enhance the effcacy of type I IFNs. Using an in vitro screening assay for new inhibitors of SHP2 phosphatase, we found that quercetin was a potent inhibitor of SHP2. Computational modeling showed that quercetin exhibited an orientation favorable to nucleophilic attack in the phosphatase domain of SHP2...
December 26, 2017: Oncotarget
Enis Kostallari, Petra Hirsova, Alena Prasnicka, Vikas K Verma, Usman Yaqoob, Nicha Wongjarupong, Lewis R Roberts, Vijay H Shah
Liver fibrosis is characterized by the activation and migration of hepatic stellate cells (HSCs) followed by matrix deposition. Recently, several studies have shown the importance of extracellular vesicles (EVs) derived from liver cells, such as hepatocytes and endothelial cells, in liver pathobiology. While most of the studies describe how liver cells modulate HSC behavior, an important gap exists in the understanding of HSC-derived signals and more specifically HSC-derived EVs in liver fibrosis. Here, we investigated the molecules released through HSC-derived EVs, the mechanism of their release and the role of these EVs in fibrosis...
January 23, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Tamica N Collins, Yingyu Mao, Hongge Li, Michael Bouaziz, Angela Hong, Gen-Sheng Feng, Fen Wang, Lawrence A Quilliam, Lin Chen, Taeju Park, Tom Curran, Xin Zhang
Specific cell shapes are fundamental to the organization and function of multicellular organisms. Fibroblast Growth Factor (FGF) signaling induces the elongation of lens fiber cells during vertebrate lens development. Nonetheless, exactly how this extracellular FGF signal is transmitted to the cytoskeletal network has previously not been determined. Here, we show that the Crk family of adaptor proteins, Crk and Crkl, are required for mouse lens morphogenesis but not differentiation. Genetic ablation and epistasis experiments demonstrated that Crk and Crkl play overlapping roles downstream of FGF signaling in order to regulate lens fiber cell elongation...
January 23, 2018: ELife
Encarnación Rodríguez-Cazorla, Samanta Ortuño-Miquel, Héctor Candela, Lindsay J Bailey-Steinitz, Martin F Yanofsky, Antonio Martínez-Laborda, Juan-José Ripoll, Antonio Vera
Ovules are fundamental for plant reproduction and crop yield as they are the precursors of seeds. Therefore, ovule specification is a critical developmental program. In Arabidopsis thaliana, ovule identity is redundantly conferred by the homeotic D-class genes SHATTERPROOF1 (SHP1), SHP2 and SEEDSTICK (STK), phylogenetically related to the MADS-domain regulatory gene AGAMOUS (AG), essential in floral organ specification. Previous studies have shown that the HUA-PEP activity, comprised of a suite of RNA-binding protein (RBP) encoding genes, regulates AG pre-mRNA processing and thus flower patterning and organ identity...
January 12, 2018: PLoS Genetics
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
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