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https://www.readbyqxmd.com/read/29782988/cholesterol-crystals-increase-vascular-permeability-by-inactivating-shp2-and-disrupting-adherens-junctions
#1
Arul M Mani, Rima Chattopadhyay, Nikhlesh K Singh, Gadiparthi N Rao
To understand the adverse effects of cholesterol crystals on vascular homeostasis, we have studied their effects on endothelial barrier function. Cholesterol crystals increased endothelial barrier permeability in a dose and time dependent manner. In addition, cholesterol crystals induced tyrosine phosphorylation of VE-cadherin and α-catenin, disrupting endothelial AJ and its barrier function and these effects required xanthine oxidase-mediated H2 O2 production, SHP2 inactivation and Frk activation. Similarly, feeding C57BL/6 mice with cholesterol-rich diet increased xanthine oxidase expression, H2 O2 production, SHP2 inactivation and Frk activation leading to enhanced tyrosine phosphorylation of VE-cadherin and α-catenin, thereby disrupting endothelial AJ and increasing vascular permeability...
May 18, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29763590/a-novel-mir17-protein-tyrosine-phosphatase-oc-epha4-regulatory-axis-of-osteoclast-activity
#2
REVIEW
Kin-Hing William Lau, Matilda H-C Sheng
Information about the molecular mechanisms leading to the activation of the osteoclast is relatively limited. While there is compelling evidence that the signaling mechanisms of Src and integrin β3 are essential for osteoclast activation, the regulation of these two signaling mechanisms is not fully understood. In this review, evidence supporting a novel regulatory axis of osteoclast activation that plays an upstream regulatory role in both the Src and integrin β3 signaling during osteoclast activation is discussed...
May 12, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29758384/disruption-of-shp1-nmda-receptor-signaling-in-spinal-cord-dorsal-horn-alleviated-inflammatory-pain
#3
Li Yang, Hu-Hu Bai, Zi-Yang Zhang, Jiang-Ping Liu, Zhan-Wei Suo, Xian Yang, Xiao-Dong Hu
Src-homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1) is one of the non-receptor-like phosphatases that are highly enriched in hematopoietic cells. Although accumulating evidence has implicated the protein tyrosine phosphatases in the regulation of nociceptive transmission and plasticity, it is largely unknown whether SHP1 was expressed in pain-related spinal cord dorsal horn and engaged in the synaptic modification of nociceptive signals. Here we found that SHP1 was present in spinal neurons of rats and functionally coupled to GluN2A subunit-containing N-methyl-d-aspartate subtype of glutamate receptors, one of the key players in central sensitization of nociceptive behaviors...
April 30, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29745030/synthesis-and-biological-evaluation-of-novel-n-aryl-%C3%AF-benzoazol-2-yl-sulfanylalkanamides-as-dual-inhibitors-of-%C3%AE-glucosidase-and-protein-tyrosine-phosphatase-1b
#4
Mei-Yan Wang, Xian-Chao Cheng, Xiu-Bo Chen, Yu Li, Lan-Lan Zang, Yu-Qing Duan, Ming-Zhu Chen, Peng Yu, Hua Sun, Run-Ling Wang
α-Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α-glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N-aryl-ω-(benzoazol-2-yl)-sulfanylalkanamides were synthesized and assayed for their α-glucosidase and PTP1B inhibitory activities, respectively...
May 9, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29706844/thyroid-cancer-detection-by-ultrasound-molecular-imaging-with-shp2-targeted-perfluorocarbon-nanoparticles
#5
ZhongQian Hu, Bin Yang, Tiankuan Li, Jia Li
Background: Contrast-enhanced ultrasound imaging has been widely used in the ultrasound diagnosis of a variety of tumours with high diagnostic accuracy, especially in patients with hepatic carcinoma, while its application is rarely reported in thyroid cancer. The currently used ultrasound contrast agents, microbubbles, cannot be targeted to molecular markers expressed in tumour cells due to their big size, leading to a big challenge for ultrasound molecular imaging. Phase-changeable perfluorocarbon nanoparticles may resolve the penetrability limitation of microbubbles and serve as a promising probe for ultrasound molecular imaging...
2018: Contrast Media & Molecular Imaging
https://www.readbyqxmd.com/read/29703160/shp2-inhibitor-phps1-protects-against-atherosclerosis-by-inhibiting-smooth-muscle-cell-proliferation
#6
Jia Chen, Zhiyong Cao, Jingshu Guan
BACKGROUND: Smooth muscle cells play an important role in the development of atherosclerosis. SHP2 is known to regulate the proliferation and migration of smooth muscle cells. The purpose of this study was to determine whether the SHP2 inhibitor PHPS1 has a pro-atherosclerotic or an atheroprotective effect in vivo and in vitro. METHODS: After exposure to a high-cholesterol diet for 4 weeks, LDL receptor-deficient (Ldlr-/- ) mice were exposed to the SHP2 inhibitor PHPS1 or vehicle...
April 27, 2018: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/29699904/tumorigenic-role-of-yap-in-hepatocellular-carcinogenesis-is-involved-in-shp2-whose-function-is-different-in-vitro-and-in-vivo
#7
Min-Kyung Kim, Jee Young Park, Yu Na Kang
Yes-associated protein (YAP) is a nuclear effector of the cell-density sensing Hippo pathway and interacts with Src homology phosphotyrosine phosphatase 2 (SHP2), which controls cell proliferation and survival. The tumor promoting/suppressing activities of YAP and SHP2 during liver tumorigenesis remain controversial. This study aimed to investigate the tumorigenic roles of YAP and SHP2 in hepatocellular carcinogenesis. Cell density associated subcellular distributions of YAP and SHP2 in normal human hepatocytes (THLE-2) and hepatocellular carcinoma (HCC) cells (SK-Hep1, SNU-182) were investigated by Western blotting and cell block immunohistochemistry...
April 21, 2018: Pathology, Research and Practice
https://www.readbyqxmd.com/read/29659837/noonan-syndrome-causing-shp2-mutants-impair-erk-dependent-chondrocyte-differentiation-during-endochondral-bone-growth
#8
Mylène Tajan, Julie Pernin-Grandjean, Nicolas Beton, Isabelle Gennero, Florence Capilla, Benjamin G Neel, Toshiyuki Araki, Philippe Valet, Maithé Tauber, Jean-Pierre Salles, Armelle Yart, Thomas Edouard
Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin-like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29651289/development-and-characterization-of-an-endotoxemia-model-in-zebra-fish
#9
Alan Y Hsu, Theodore Gurol, Tiago J P Sobreira, Sheng Zhang, Natalie Moore, Chufan Cai, Zhong-Yin Zhang, Qing Deng
Endotoxemia is a condition in which endotoxins enter the blood stream and cause systemic and sometimes lethal inflammation. Zebra fish provides a genetically tractable model organism for studying innate immunity, with additional advantages in live imaging and drug discovery. However, a bona fide endotoxemia model has not been established in zebra fish. Here, we have developed an acute endotoxemia model in zebra fish by injecting a single dose of LPS directly into the circulation. Hallmarks of human acute endotoxemia, including systemic inflammation, extensive tissue damage, circulation blockade, immune cell mobilization, and emergency hematopoiesis, were recapitulated in this model...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29644115/shp2-regulates-skeletal-cell-fate-by-modifying-sox9-expression-and-transcriptional-activity
#10
Chunlin Zuo, Lijun Wang, Raghavendra M Kamalesh, Margot E Bowen, Douglas C Moore, Mark S Dooner, Anthony M Reginato, Qian Wu, Christoph Schorl, Yueming Song, Matthew L Warman, Benjamin G Neel, Michael G Ehrlich, Wentian Yang
Chondrocytes and osteoblasts differentiate from a common mesenchymal precursor, the osteochondroprogenitor (OCP), and help build the vertebrate skeleton. The signaling pathways that control lineage commitment for OCPs are incompletely understood. We asked whether the ubiquitously expressed protein-tyrosine phosphatase SHP2 (encoded by Ptpn11 ) affects skeletal lineage commitment by conditionally deleting Ptpn11 in mouse limb and head mesenchyme using "Cre-loxP"-mediated gene excision. SHP2-deficient mice have increased cartilage mass and deficient ossification, suggesting that SHP2-deficient OCPs become chondrocytes and not osteoblasts...
2018: Bone Research
https://www.readbyqxmd.com/read/29568093/selective-inhibition-of-leukemia-associated-shp2-e69k-mutant-by-the-allosteric-shp2-inhibitor-shp099
#11
X Sun, Y Ren, S Gunawan, P Teng, Z Chen, H R Lawrence, J Cai, N J Lawrence, J Wu
No abstract text is available yet for this article.
May 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29565710/deletion-of-mbd2-inhibits-proliferation-of-chronic-myeloid-leukaemia-blast-phase-cells
#12
Ling Cheng, Ying Tang, Xing Chen, Lei Zhao, Songya Liu, Yanna Ma, Na Wang, Kuangguo Zhou, Jianfeng Zhou, Mi Zhou
Aberrant methylation of tumour suppressor genes is associated with the progression to a blast crisis in chronic myeloid leukaemia (CML). Methyl-CpG-binding domain protein 2 (MBD2) has been studied as a "reader" of DNA methylation in many cancers, but its role in CML is unclear. We constructed cell models of a homozygous deletion mutation of MBD2 using gene-editing technology in K562 cells and BV173 cells. Here, we demonstrated that the deletion of MBD2 inhibited cell proliferation capacity in vitro...
March 22, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29559584/gain-of-function-mutations-in-the-gene-encoding-the-tyrosine-phosphatase-shp2-induce-hydrocephalus-in-a-catalytically-dependent-manner
#13
Hong Zheng, Wen-Mei Yu, Ronald R Waclaw, Maria I Kontaridis, Benjamin G Neel, Cheng-Kui Qu
Catalytically activating mutations in Ptpn11 , which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations on the development of hydrocephalus in the mouse...
March 20, 2018: Science Signaling
https://www.readbyqxmd.com/read/29555699/a-quorum-sensing-regulated-protein-binds-cell-wall-components-and-enhances-lysozyme-resistance-in-streptococcus-pyogenes
#14
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...
June 1, 2018: Journal of Bacteriology
https://www.readbyqxmd.com/read/29535161/igf-i-receptor-signaling-pathways
#15
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
https://www.readbyqxmd.com/read/29523509/shp2-inhibition-may-resensitize-nsclc-tumors-to-alk-inhibitors
#16
(no author information available yet)
Targeting SHP2 suppresses ALK inhibitor resistance caused by tyrosine kinase reactivation.
May 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29505847/shp2-deletion-in-hepatocytes-suppresses-hepatocarcinogenesis-driven-by-oncogenic-%C3%AE-catenin-pik3ca-and-met
#17
Jacey J Liu, Yanjie Li, Wendy S Chen, Yan Liang, Gaowei Wang, Min Zong, Kota Kaneko, Ruiyun Xu, Michael Karin, Gen-Sheng Feng
BACKGROUND & 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 carcinogens 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
https://www.readbyqxmd.com/read/29505033/shp2-inhibition-restores-sensitivity-in-alk-rearranged-non-small-cell-lung-cancer-resistant-to-alk-inhibitors
#18
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...
May 2018: Nature Medicine
https://www.readbyqxmd.com/read/29494926/scaffold-based-novel-shp2-allosteric-inhibitors-design-using-receptor-ligand-pharmacophore-model-virtual-screening-and-molecular-dynamics
#19
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...
April 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29483824/dioscin-overcome-tki-resistance-in-egfr-mutated-lung-adenocarcinoma-cells-via-down-regulation-of-tyrosine-phosphatase-shp2-expression
#20
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
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