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https://www.readbyqxmd.com/read/29156682/pharmacologic-inhibition-of-pi3k-p110%C3%AE-in-mutant-shp2e76k-expressing-mice
#1
Lisa Deng, Elizabeth L Virts, Reuben Kapur, Rebecca J Chan
Juvenile myelomonocytic leukemia is a childhood malignancy that lacks effective chemotherapies and thus has poor patient outcomes. PI3K p110δ has been found to promote hyperproliferation of cells expressing mutant Shp2. In this study, we tested the efficacy of a PI3Kδ inhibitor in mice expressing the Shp2 gain-of-function mutation, E76K. We found that in vivo treatment of mice led to significantly decreased splenomegaly, reduced frequency of bone marrow progenitor cells, and increased terminally differentiated peripheral blood myeloid cells...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29155585/allosteric-inhibitors-of-shp2-with-therapeutic-potential-for-cancer-treatment
#2
Jingjing Xie, Xiaojia Si, Shoulai Gu, Mingliang Wang, Jian Shen, Haoyan Li, Jian Shen, Dan Li, Yanjia Fang, Cong Liu, Jidong Zhu
SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, is involved in multiple cell signaling processes including Ras/MAPK and Hippo/YAP pathways. SHP2 has been shown to contribute to the progression of a number of cancer types including leukemia, gastric and breast cancer. It also regulates T-cell activation by interacting with inhibitory immune checkpoint receptors such as the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have drawn great attention by both inhibiting tumor cell proliferation and activating T cell immune responses toward cancer cells...
November 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29125235/comparison-of-the-mrna-expression-profile-of-b-cell-receptor-components-in-normal-cd5-high-b-lymphocytes-and-chronic-lymphocytic-leukemia-a-key-role-of-zap70
#3
Aleena A Gladkikh, Daria M Potashnikova, Victor Tatarskiy, Margarita Yastrebova, Alvina Khamidullina, Natasha Barteneva, Ivan Vorobjev
The B-cell receptor (BCR) signaling pathway is of great importance for B-cell survival and proliferation. The BCR expressed on malignant B-CLL cells contributes to the disease pathogenesis, and its signaling pathway is currently the target of several therapeutic strategies. Although various BCR alterations have been described in B-CLL at the protein level, the mRNA expression levels of tyrosine kinases in B-CLL compared to that in normal CD5-high and CD5-low B-lymphocytes remain unknown. In the current study, we measured the mRNA expression levels of CD79A, CD79B, LYN, SYK, SHP1, and ZAP70 in purified populations of CD5-high B-CLL cells, CD5-low B-cells from the peripheral blood of healthy donors, and CD5-high B-cells from human tonsils...
November 10, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29125030/exploring-the-effect-of-d61g-mutation-on-shp2-cause-gain-of-function-activity-by-a-molecular-dynamics-study
#4
Hong-Lian Li, Ying Ma, Chang-Jie Zheng, Wen-Yan Jin, Wen-Shan Liu, Run-Ling Wang
Noonan syndrome (NS) is a common autosomal dominant congenital disorder which could cause the congenital cardiopathy and cancer predisposition. Previous studies reported that the knock-in mouse models of the mutant D61G of SHP2 exhibited the major features of NS, which demonstrated that the mutation D61G of SHP2 could cause NS. To explore the effect of D61G mutation on SHP2 and explain the high activity of the mutant, molecular dynamic (MD) simulations were performed on wild type (WT) of SHP2 and the mutated SHP2-D61G, respectively...
November 10, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29109244/expression-of-concern-prep1-controls-insulin-glucoregulatory-function-in-liver-by-transcriptional-targeting-of-shp1-tyrosine-phosphatase-diabetes-2011-60-138-147-doi-https-doi-org-10-2337-db10-0860-pmid-20864515
#5
Francesco Oriente, Salvatore Iovino, Serena Cabaro, Angela Cassese, Elena Longobardi, Claudia Miele, Paola Ungaro, Pietro Formisano, Francesco Blasi, Francesco Beguinot
No abstract text is available yet for this article.
November 6, 2017: Diabetes
https://www.readbyqxmd.com/read/29103443/protein-and-mrna-expressions-of-il-6-and-its-key-signaling-factors-under-orthodontic-forces-in-mice-an-in-vivo-study
#6
Yi Liu, Fang Song, Shu Wu, Shushu He, Mingmei Meng, Chunxiao Lv, Qingqing Yang, Song Chen
INTRODUCTION: The purpose of this study was to investigate the mechanical loading-induced changes in protein and mRNA expressions of interleukin-6 (IL-6) and its key signaling factors glycoprotein 130 (gp130), signal transducer and activator of transcription 3 (STAT3), and the Src homology phosphotyrosine phosphatase (SHP2) at the tension and compression sides of the teeth in mouse models. METHODS: A total of 55 C57B/6 mice (10 weeks old) were divided into 3 groups...
November 2017: American Journal of Orthodontics and Dentofacial Orthopedics
https://www.readbyqxmd.com/read/29100798/benzo-c-1-2-5-thiadiazole-derivatives-a-new-class-of-potent-src-homology-2-domain-containing-protein-tyrosine-phosphatase-2-shp2-inhibitors
#7
Wen-Long Wang, Xiao-Yu Chen, Ya Gao, Li-Xin Gao, Li Sheng, Jingyu Zhu, Lei Xu, Zhen-Zhong Ding, Chao Zhang, Jing-Ya Li, Jia Li, Yu-Bo Zhou
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase linked to various kinds of cancers. Consequently, SHP2 has emerged as a promising target for novel anti-cancer agents. Using scaffold-hopping strategy, a series of benzo[c][1,2,5]thiadiazole derivatives was designed from PTP1B inhibitors with 1H-2,3-Dihydroperimidine motif, synthesized and evaluated their biological activities against PTP1B and SHP2. Among them, the representative compound 11g displayed SHP2 inhibitory activity with IC50 of 2...
October 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29091299/hepatic-leukocyte-immunoglobulin-like-receptor-b4-lilrb4-attenuates-nonalcoholic-fatty-liver-disease-via-shp1-traf6-pathway
#8
Yao Lu, Zhou Jiang, Haijiang Dai, Rujia Miao, Jingxian Shu, Haotian Gu, Xing Liu, Zhijun Huang, Guoping Yang, Alex F Chen, Hong Yuan, Ying Li, Jingjing Cai
Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver pathology marked by hepatic steatosis and commonly accompanied by systematic inflammation and metabolic disorder. Despite an accumulating number of studies, no pharmacological strategy is available to treat this condition in the clinic. The current work applied extensive gain- and loss-of-function approaches to identify the key immune factor leukocyte immunoglobulin-like receptor B4 (LILRB4) as a negative regulator of NAFLD. The hepatocyte-specific knockout of LILRB4 (LILRB4-HKO) significantly exacerbated high-fat diet (HFD)-induced insulin resistance, glucose metabolic imbalance, hepatic lipid accumulation, and systematic inflammation in mice, whereas LILRB4 overexpression in hepatocytes showed a completely opposite phenotype relative to that of LILRB4-HKO mice when compared to their corresponding controls...
November 1, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29089257/identification-of-an-allosteric-benzothiazolopyrimidone-inhibitor-of-the-oncogenic-protein-tyrosine-phosphatase-shp2
#9
Jonathan R LaRochelle, Michelle Fodor, Jana M Ellegast, Xiaoxi Liu, Vidyasiri Vemulapalli, Morvarid Mohseni, Travis Stams, Sara J Buhrlage, Kimberly Stegmaier, Matthew J LaMarche, Michael G Acker, Stephen C Blacklow
The PTPN11 oncogene encodes the cytoplasmic protein tyrosine phosphatase SHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignancies and other cancers. Here, we employ high-throughput screening to discover a lead chemical scaffold, the benzothiazolopyrimidones, that allosterically inhibits this oncogenic phosphatase by simultaneously engaging the C-SH2 and PTP domains. We improved our lead to generate an analogue that better suppresses SHP2 activity in vitro...
October 20, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29046360/a-erk-rsk-mediated-negative-feedback-loop-regulates-m-csf-evoked-pi3k-akt-activation-in-macrophages
#10
Lijun Wang, Caterina Iorio, Kevin Yan, Howard Yang, Sunao Takeshita, Sumin Kang, Benjamin G Neel, Wentian Yang
Activation of the RAS/ERK and its downstream signaling components is essential for growth factor-induced cell survival, proliferation, and differentiation. The Src homology-2 domain containing protein tyrosine phosphatase 2 (SHP2), encoded by protein tyrosine phosphatase, non-receptor type 11 (Ptpn11), is a positive mediator required for most, if not all, receptor tyrosine kinase-evoked RAS/ERK activation, but differentially regulates the PI3K/AKT signaling cascade in various cellular contexts. The precise mechanisms underlying the differential effects of SHP2 deficiency on the PI3K pathway remain unclear...
October 18, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29028795/alx4-relays-sequential-fgf-signaling-to-induce-lacrimal-gland-morphogenesis
#11
Ankur Garg, Mukesh Bansal, Noriko Gotoh, Gen-Sheng Feng, Jian Zhong, Fen Wang, Ariana Kariminejad, Steven Brooks, Xin Zhang
The sequential use of signaling pathways is essential for the guidance of pluripotent progenitors into diverse cell fates. Here, we show that Shp2 exclusively mediates FGF but not PDGF signaling in the neural crest to control lacrimal gland development. In addition to preventing p53-independent apoptosis and promoting the migration of Sox10-expressing neural crests, Shp2 is also required for expression of the homeodomain transcription factor Alx4, which directly controls Fgf10 expression in the periocular mesenchyme that is necessary for lacrimal gland induction...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28983104/shp2-regulates-the-osteogenic-fate-of-growth-plate-hypertrophic-chondrocytes
#12
Lijun Wang, Jiahui Huang, Douglas C Moore, Chunlin Zuo, Qian Wu, Liqin Xie, Klaus von der Mark, Xin Yuan, Di Chen, Matthew L Warman, Michael G Ehrlich, Wentian Yang
Transdifferentiation of hypertrophic chondrocytes into bone-forming osteoblasts has been reported, yet the underlying molecular mechanism remains incompletely understood. SHP2 is an ubiquitously expressed cytoplasmic protein tyrosine phosphatase. SHP2 loss-of-function mutations in chondroid cells are linked to metachondromatosis in humans and mice, suggesting a crucial role for SHP2 in the skeleton. However, the specific role of SHP2 in skeletal cells has not been elucidated. To approach this question, we ablated SHP2 in collagen 2α1(Col2α1)-Cre- and collagen 10α1(Col10α1)-Cre-expressing cells, predominantly proliferating and hypertrophic chondrocytes, using "Cre-loxP"-mediated gene excision...
October 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28930683/differential-mechanisms-for-shp2-binding-and-activation-are-exploited-by-geographically-distinct-helicobacter-pylori-caga-oncoproteins
#13
Takeru Hayashi, Miki Senda, Nobuhiro Suzuki, Hiroko Nishikawa, Chi Ben, Chao Tang, Lisa Nagase, Kaori Inoue, Toshiya Senda, Masanori Hatakeyama
Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28929581/gain-of-function-mutation-in-ptpn11-in-histiocytic-sarcomas-of-bernese-mountain-dogs
#14
T Thaiwong, S Sirivisoot, M Takada, V Yuzbasiyan-Gurkan, M Kiupel
Histiocytic sarcoma (HS) is an aggressive malignant neoplasm of dendritic cell origin that is common in certain breeds of dogs. High prevalence of fatal, disseminated HS has been described in Bernese Mountain Dogs (BMDs). Support for genetic predisposition to develop HS has been presented in several studies, but to date, causative genetic events have not been reported. In addition, no driver mutations have been identified in tumours. Recently, E76K gain-of-function mutation in SHP2 encoded by the PTPN11 gene has been described in human histiocytic malignancies...
September 20, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28911943/heterozygous-deletion-of-akt1-rescues-cardiac-contractility-but-not-hypertrophy-in-a-mouse-model-of-noonan-syndrome-with-multiple-lentigines
#15
Rajika Roy, Maike Krenz
Noonan Syndrome with Multiple Lentigines (NSML) is associated with congenital heart disease in form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Genetically, NSML is primarily caused by mutations in the non-receptor protein tyrosine phosphatase SHP2. Importantly, certain SHP2 mutations such as Q510E can cause a particularly severe form of HCM with heart failure in infancy. Due to lack of insight into the underlying pathomechanisms, an effective custom-tailored therapy to prevent heart failure in these patients has not yet been found...
November 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28887433/the-neurobeachin-like-2-protein-regulates-mast-cell-homeostasis
#16
Sebastian Drube, Randy Grimlowski, Carsten Deppermann, Julia Fröbel, Florian Kraft, Nico Andreas, David Stegner, Jan Dudeck, Franziska Weber, Mandy Rödiger, Christiane Göpfert, Julia Drube, Daniela Reich, Bernhard Nieswandt, Anne Dudeck, Thomas Kamradt
The neurobeachin-like 2 protein (Nbeal2) belongs to the family of beige and Chediak-Higashi (BEACH) domain proteins. Loss-of-function mutations in the human NBEAL2 gene or Nbeal2 deficiency in mice cause gray platelet syndrome, a bleeding disorder characterized by macrothrombocytopenia, splenomegaly, and paucity of α-granules in megakaryocytes and platelets. We found that in mast cells, Nbeal2 regulates the activation of the Shp1-STAT5 signaling axis and the composition of the c-Kit/STAT signalosome. Furthermore, Nbeal2 mediates granule formation and restricts the expression of the transcription factors, IRF8, GATA2, and MITF as well as of the cell-cycle inhibitor p27, which are essential for mast cell differentiation, proliferation, and cytokine production...
October 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28883531/engineered-proteins-with-sensing-and-activating-modules-for-automated-reprogramming-of-cellular-functions
#17
Jie Sun, Lei Lei, Chih-Ming Tsai, Yi Wang, Yiwen Shi, Mingxing Ouyang, Shaoying Lu, Jihye Seong, Tae-Jin Kim, Pengzhi Wang, Min Huang, Xiangdong Xu, Victor Nizet, Shu Chien, Yingxiao Wang
Protein-based biosensors or activators have been engineered to visualize molecular signals or manipulate cellular functions. Here we integrate these two functionalities into one protein molecule, an integrated sensing and activating protein (iSNAP). A prototype that can detect tyrosine phosphorylation and immediately activate auto-inhibited Shp2 phosphatase, Shp2-iSNAP, is designed through modular assembly. When Shp2-iSNAP is fused to the SIRPα receptor which typically transduces anti-phagocytic signals from the 'don't eat me' CD47 ligand through negative Shp1 signaling, the engineered macrophages not only allow visualization of SIRPα phosphorylation upon CD47 engagement but also rewire the CD47-SIRPα axis into the positive Shp2 signaling, which enhances phagocytosis of opsonized tumor cells...
September 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28881828/shp2-negatively-regulates-hla-abc-and-pd-l1-expression-via-stat1-phosphorylation-in-prostate-cancer-cells
#18
Zhuqing Liu, Yu Zhao, Juemin Fang, Ran Cui, Yuanyuan Xiao, Qing Xu
Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitous protein tyrosine phosphatase that activates the signal transduction pathways of several growth factors and cytokines. In our study, SHP2 expression was very high in prostate cancer (PCa) cell lines, and the expression of phospho-signal transducer and activator of transcription 1 (p-STAT1) and STAT1 was very low. SHP2 knockdown upregulated the expression of p-STAT1 and downregulated phospho-extracellular signal regulated kinase (p-ERK)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878211/assay-to-visualize-specific-protein-oxidation-reveals-spatio-temporal-regulation-of-shp2
#19
Ryouhei Tsutsumi, Jana Harizanova, Rabea Stockert, Katrin Schröder, Philippe I H Bastiaens, Benjamin G Neel
Reactive oxygen species are produced transiently in response to cell stimuli, and function as second messengers that oxidize target proteins. Protein-tyrosine phosphatases are important reactive oxygen species targets, whose oxidation results in rapid, reversible, catalytic inactivation. Despite increasing evidence for the importance of protein-tyrosine phosphatase oxidation in signal transduction, the cell biological details of reactive oxygen species-catalyzed protein-tyrosine phosphatase inactivation have remained largely unclear, due to our inability to visualize protein-tyrosine phosphatase oxidation in cells...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28874583/smad7-enables-stat3-activation-and-promotes-pluripotency-independent-of-tgf-%C3%AE-signaling
#20
Yi Yu, Shuchen Gu, Wenjian Li, Chuang Sun, Fenfang Chen, Mu Xiao, Lei Wang, Dewei Xu, Ye Li, Chen Ding, Zongping Xia, Yi Li, Sheng Ye, Pinglong Xu, Bin Zhao, Jun Qin, Ye-Guang Chen, Xia Lin, Xin-Hua Feng
Smad7 is a negative feedback product of TGF-β superfamily signaling and fine tunes a plethora of pleiotropic responses induced by TGF-β ligands. However, its noncanonical functions independent of TGF-β signaling remain to be elucidated. Here, we show that Smad7 activates signal transducers and activators of transcription 3 (STAT3) signaling in maintaining mouse embryonic stem cell pluripotency in a manner independent of the TGF-β receptors, yet dependent on the leukemia inhibitory factor (LIF) coreceptor glycoprotein 130 (gp130)...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
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