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Shp1 OR Shp2

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https://www.readbyqxmd.com/read/28930683/differential-mechanisms-for-shp2-binding-and-activation-are-exploited-by-geographically-distinct-helicobacter-pylori-caga-oncoproteins
#1
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
#2
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
#3
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...
September 11, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28887433/the-neurobeachin-like-2-protein-regulates-mast-cell-homeostasis
#4
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...
September 8, 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
#5
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
#6
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
#7
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
#8
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 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28873070/functional-assessment-of-genetic-variants-located-in-the-promoter-of-shp1-nr0b2
#9
Katharina Prestin, Maria Olbert, Janine Hussner, Henry Völzke, Henriette E Meyer Zu Schwabedissen
Small heterodimer partner 1 (SHP1, NR0B2) is a member of the superfamily of nuclear receptors (NRs). Even if this orphan receptor, unlike other NRs, lacks the DNA-binding domain, it is capable of regulating transcription by repressing the activity of other NRs by direct protein-protein interaction. Accordingly, SHP1 is part of negative feedback loops of the transcriptional regulation of genes involved in drug metabolism and various metabolic pathways including bile acid and glucose homeostasis. Although it is known that several interacting partners of SHP1 also modulate its expression, there is little information about genetic variability of this regulatory mechanism...
August 31, 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28870898/inhibitory-activity-of-iron-chelators-ata-and-dfo-on-mcf-7-breast-cancer-cells-and-phosphatases-ptp1b-and-shp2
#10
Alicja Kuban-Jankowska, Kamlesh K Sahu, Magdalena Gorska-Ponikowska, Jack A Tuszynski, Michal Wozniak
BACKGROUND: Rapidly-dividing cancer cells have higher requirement for iron compared to non-transformed cells, making iron chelating a potential anticancer strategy. In the present study we compared the anticancer activity of uncommon iron chelator aurintricarboxylic acid (ATA) with the known deferoxamine (DFO). MATERIALS AND METHODS: We investigated the impact of ATA and DFO on the viability and proliferation of MCF-7 cancer cells. Moreover we performed enzymatic activity assays and computational analysis of the ATA and DFO effects on pro-oncogenic phosphatases PTP1B and SHP2...
September 2017: Anticancer Research
https://www.readbyqxmd.com/read/28855209/therapeutic-targeting-of-oncogenic-tyrosine-phosphatases
#11
Rochelle Frankson, Zhi-Hong Yu, Yunpeng Bai, Qinglin Li, Ruo-Yu Zhang, Zhong-Yin Zhang
Protein tyrosine phosphatases (PTPs) are exciting and novel targets for cancer drug discovery that work in concert with protein tyrosine kinases (PTKs) in controlling cellular homeostasis. Given the activating role that some PTKs play in initiating growth factor-mediated cellular processes, PTPs are usually perceived as the negative regulators of these events and therefore tumor suppressive in nature. However, mounting evidence indicate that PTPs do not always antagonize the activity of PTKs in regulating tyrosine phosphorylation, but can also play dominant roles in the initiation and progression of signaling cascades that regulate cell functions...
August 30, 2017: Cancer Research
https://www.readbyqxmd.com/read/28852935/shp2-regulates-proliferation-and-tumorigenicity-of-glioma-stem-cells
#12
Laura Roccograndi, Zev A Binder, Logan Zhang, Nicola Aceto, Zhuo Zhang, Mohamed Bentires-Alj, Ichiro Nakano, Nadia Dahmane, Donald M O'Rourke
SHP2 is a cytoplasmic protein tyrosine phosphatase (PTPase) involved in multiple signaling pathways and was the first identified proto-oncogene PTPase. Previous work in glioblastoma (GBM) has demonstrated the role of SHP2 PTPase activity in modulating the oncogenic phenotype of adherent GBM cell lines. Mutations in PTPN11, the gene encoding SHP2, have been identified with increasing frequency in GBM. Given the importance of SHP2 in developing neural stem cells, and the importance of glioma stem cells (GSCs) in GBM oncogenesis, we explored the functional role of SHP2 in GSCs...
August 29, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28833338/reptin-regulates-insulin-stimulated-akt-phosphorylation-in-hepatocellular-carcinoma-via-the-regulation-of-shp-1-ptpn6
#13
Anne-Aurélie Raymond, Joaquim Javary, Osman Breig, Véronique Neaud, Jean Rosenbaum
Hepatocellular carcinoma (HCC) is the main primary cancer of the liver. Many studies have shown that insulin resistance is a risk factor for HCC. We previously discovered the overexpression and oncogenic role of the Reptin/RUVBL2 ATPase in HCC. Here, we found that Reptin silencing enhanced insulin sensitivity in 2 HCC cell lines, as shown by a large potentiation of insulin-induced AKT phosphorylation on Ser473 and Thr308, and of downstream signalling. Reptin silencing did not affect the tyrosine phosphorylation of the insulin receptor nor of IRS1, but it enhanced the tyrosine phosphorylation of the p85 subunit of PI3K...
August 22, 2017: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/28814887/shp2-overexpression-enhances-the-invasion-and-metastasis-of-ovarian-cancer-in-vitro-and-in-vivo
#14
ZhongQian Hu, Jia Li, Qi Gao, Shuping Wei, Bin Yang
PURPOSE: SHP2 has roles in a variety of signal transduction pathways and in many important cellular processes, including proliferation, differentiation, movement regulation, and apoptosis. In addition, SHP2 expression is closely associated with multiple types of malignancies. In this study, we examined the role of SHP2 in epithelial ovarian cancer. PATIENTS AND METHODS: SHP2 expression in cancer and normal ovarian tissue specimens was evaluated by immunohistochemical staining and Western blot analyses...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28814789/differential-oxidation-of-protein-tyrosine-phosphatases-during-zebrafish-caudal-fin-regeneration
#15
Wei Wu, Alexander James Hale, Simone Lemeer, Jeroen den Hertog
Zebrafish have the capacity to regenerate lost tissues and organs. Amputation of the caudal fin results in a rapid, transient increase in H2O2 levels emanating from the wound margin, which is essential for regeneration, because quenching of reactive oxygen species blocks regeneration. Protein-tyrosine phosphatases (PTPs) have a central role in cell signalling and are susceptible to oxidation, which results in transient inactivation of their catalytic activity. We hypothesized that PTPs may become oxidized in response to amputation of the caudal fin...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28814604/macrophage-restricted-shp2-tyrosine-phosphatase-acts-as-a-rheostat-for-mmp12-through-tgf-%C3%AE-activation-in-the-prevention-of-age-related-emphysema-in-mice
#16
Jiaqi Xu, Bo Tao, Xiaohong Guo, Shiyi Zhou, Yongda Li, Yuqin Zhang, Zanhua Zhou, Hongqiang Cheng, Xue Zhang, Yuehai Ke
Persistent activation of macrophages in lungs plays a critical role in the production of matrix metalloproteinases (MMPs) that contributes to the destruction of alveolar walls, a hallmark for pulmonary emphysema. Dysregulated TGF-β1 signaling has been an essential determinant in the elevation of MMPs during the development of emphysema. Nevertheless, the mechanism for this MMP-dependent pathogenesis has yet to be clearly investigated. Recently, we identified an important role for tyrosine phosphatase Src homology domain-containing protein tyrosine phosphatase 2 (Shp2) in regulating the activation of alveolar macrophages...
August 16, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28804122/shp2-is-required-for-bcr-abl1-induced-hematologic-neoplasia
#17
S Gu, A Sayad, G Chan, W Yang, Z Lu, C Virtanen, R A Van Etten, B G Neel
BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph(+)) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation models for CML and BCR-ABL1(+) B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia...
August 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28768764/src-homology-2-domain-containing-phosphotyrosine-phosphatase-2-shp2-controls-surface-glua1-in-synaptic-homeostasis
#18
Bin Zhang, Wen Lu
Src Homology 2 Domain Containing Phosphotyrosine Phosphatase 2 (Shp2) functions in synaptic plasticity, learning, and memory. However, the precise mechanisms by which this multifunctional protein contributes to synaptic function remains largely unknown. Homeostatic plasticity may be viewed as a process of bi-directional synaptic scaling, up or down. Through this process neuronal circuitry stability is maintained so that changes in synaptic strength may be preserved under changing conditions. Better understanding of these processes is needed...
August 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28761355/ergosterol-peroxide-inhibits-ovarian-cancer-cell-growth-through-multiple-pathways
#19
Weiwei Tan, Meihong Pan, Hui Liu, Hequn Tian, Qing Ye, Hongda Liu
Ergosterol peroxide (EP), a sterol derived from medicinal mushrooms, has been reported to exert antitumor activity in several tumor types. However, the role of EP toward ovarian cancer cells has not been investigated. In this study, we analyzed the cytotoxicity of EP in various cell lines representing high-grade serous ovarian cancer and low-grade serous ovarian cancer, respectively. Although EP showed no significant inhibition of the viability of normal ovarian surface epithelial cells, it impaired the proliferation and invasion capacities of tumor cells in a dose-dependent manner...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28754897/reciprocal-regulation-of-tlr2-mediated-ifn-%C3%AE-production-by-shp2-and-gsk3%C3%AE
#20
Jin Hee Park, Ryeojin Ko, Soo Young Lee
Toll-like receptor 2 (TLR2) mediates the innate immune response to bacterial lipopeptides and peptidoglycans by stimulating the production of inflammatory cytokines. However, the mechanisms by which TLR2 signaling regulates type I interferon (IFN)-β production are poorly understood. Here, we identified Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) as a negative regulator of TLR2-induced IFN-β production. Pharmacological inhibition or reduced expression of SHP2 potentiated TLR2 agonist-mediated IFN-β transcription and STAT1 activation, whereas overexpression of SHP2 impaired IFN-β transcription and STAT1 activation...
July 28, 2017: Scientific Reports
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