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https://www.readbyqxmd.com/read/28424251/nuclear-shp2-directs-normal-embryo-implantation-via-facilitating-the-er%C3%AE-tyrosine-phosphorylation-by-the-src-kinase
#1
Hao Ran, Shuangbo Kong, Shuang Zhang, Jianghong Cheng, Chan Zhou, Bo He, Qiliang Xin, John P Lydon, Francesco J DeMayo, Gen-Sheng Feng, Guoliang Xia, Zhongxian Lu, Chao Wang, Haibin Wang
Estrogen and progesterone coupled with locally produced signaling molecules are essential for embryo implantation. However, the hierarchical landscape of the molecular pathways that governs this process remains largely unexplored. Here we show that the protein tyrosine phosphatase Shp2, a positive transducer of RTK signaling, is predominately localized in the nuclei in the periimplantation mouse uterus. Uterine-specific deletion of Shp2 exhibits reduced progesterone receptor (PR) expression and progesterone resistance, which derails normal uterine receptivity, leading to complete implantation failure in mice...
April 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28423588/shp2-confers-cisplatin-resistance-in-small-cell-lung-cancer-via-an-akt-mediated-increase-in-ca916798
#2
Xuemei Yang, Chunlan Tang, Hu Luo, Haijing Wang, Xiangdong Zhou
The tyrosine phosphatase Shp2 is associated with tumorigenesis in small cell lung cancer (SCLC). However, the relationship between Shp2 and resistance to chemotherapy remains unclear. Here, we show that Shp2 plays an important role in inducing resistance to cisplatin-based chemotherapy via the SHP2-AKT-CA916798 pathway. In an SCLC cell line, overexpression of Shp2 induced cisplatin resistance and the increased expression of AKT, pAKT, pmTOR, and CA916798. Conversely, depletion of Shp2 in a cisplatin-resistant cell line via RNA interference increased cisplatin sensitivity and decreased AKT, pAKT, pmTOR, and CA916798 expression levels...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416389/shp1-positively-regulates-egfr-signaling-by-controlling-egfr-protein-expression-in-mammary-epithelial-cells
#3
Taichang Yuan, Hua Ma, Zhuanyun Du, Xusheng Xiong, Hongwei Gao, Zenghui Fang, Licai He, Hongzhi Li, Haihua Gu
SH2-domain containing protein tyrosine phosphatase 1 (Shp1/PTPN6) is mainly expressed in hematopoietic cells and acts a negative signaling regulator. Although Shp1 is also expressed in epithelial cells, the function of shp1 in normal epithelial is still less well understood, especially in regulating the growth of epithelial cells. In this study, different shRNAs and siRNAs against Shp1were used to knockdown Shp1 expression in MCF10A, an immortalized mammary epithelial cell line. Shp1 knockdown resulted in inhibited cell growth in part due to lower percentage of MCF10A cells entering into S phase and reduced cyclin D1 expression...
April 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28413197/structure-and-function-of-helicobacter-pylori-caga-the-first-identified-bacterial-protein-involved-in-human-cancer
#4
REVIEW
Masanori Hatakeyama
Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor of gastric cancer. The cagA gene-encoded CagA protein is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Delivered CagA then acts as a non-physiological scaffold/hub protein by interacting with multiple host signaling molecules, most notably the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1/MARK, in both tyrosine phosphorylation-dependent and -independent manners...
2017: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
https://www.readbyqxmd.com/read/28410990/tyrosine-kinase-syk-licenses-myd88-adaptor-protein-to-instigate-il-1%C3%AE-mediated-inflammatory-disease
#5
Prajwal Gurung, Gaofeng Fan, John R Lukens, Peter Vogel, Nicholas K Tonks, Thirumala-Devi Kanneganti
Mice carrying a hypomorphic point mutation in the Ptpn6 gene (Ptpn6(spin) mice) develop an inflammatory skin disease that resembles neutrophilic dermatosis in humans. Here, we demonstrated that interleukin-1α (IL-1α) signaling through IL-1R and MyD88 in both stromal and immune cells drive inflammation in Ptpn6(spin) mice. We further identified SYK as a critical kinase that phosphorylates MyD88, promoted MyD88-dependent signaling and mediates dermatosis in Ptpn6(spin) mice. Our studies further demonstrated that SHP1 encoded by Ptpn6 binds and suppresses SYK activation to inhibit MyD88 phosphorylation...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28406453/sequence-polymorphism-and-intrinsic-structural-disorder-as-related-to-pathobiological-performance-of-the-helicobacter-pylori-caga-oncoprotein
#6
REVIEW
Hiroko Nishikawa, Masanori Hatakeyama
CagA, an oncogenic virulence factor produced by Helicobacter pylori, is causally associated with the development of gastrointestinal diseases such as chronic gastritis, peptic ulcers, and gastric cancer. Upon delivery into gastric epithelial cells via bacterial type IV secretion, CagA interacts with a number of host proteins through the intrinsically disordered C-terminal tail, which contains two repeatable protein-binding motifs, the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif and the CagA multimerization (CM) motif...
April 13, 2017: Toxins
https://www.readbyqxmd.com/read/28403515/an-aggressive-multifocal-primary-cns-histiocytosis-with-ptpn11-shp2-mutation
#7
Qi Zhang, Areej Shibani, Bekim Sadikovic, Christopher J Howlett, Lee-Cyn Ang
Primary histiocytic tumors of the CNS are rare. The current WHO classification (2016) included 5 entities: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and histiocytic sarcoma (HS) (1). The diagnosis usually is made based on the tumor differentiation as to the counterpart in normal histiocyte development. This article is protected by copyright. All rights reserved.
April 12, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28388567/synthesis-bioactivity-3d-qsar-studies-of-novel-dibenzofuran-derivatives-as-ptp-meg2-inhibitors
#8
Ying Ma, Hui-Yu Wei, Yu-Ze Zhang, Wen-Yan Jin, Hong-Lian Li, Hui-Zhou, Xian-Chao Cheng, Run-Ling Wang
PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 μM). By means of the powerful ''HipHop'' technique, a 3D-QSAR study was carried out to explore structure activity relationship of these molecules...
March 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28372909/y-shaped-bis-arylethenesulfonic-acid-esters-potential-potent-and-membrane-permeable-protein-tyrosine-phosphatase-1b-inhibitors
#9
Fengzhi Yang, Fangzhou Xie, Ying Zhang, Yu Xia, Wenlu Liu, Faqin Jiang, Celine Lam, Yixue Qiao, Dongsheng Xie, Jianqi Li, Lei Fu
Known PTP1B inhibitors with bis-anionic moieties exhibit potent inhibitory activity, good selectivity, however, they are incapable of penetrating cellular membranes. Based upon our finding of a new pharmacophoric group in inhibition of PTP1B and the structural characteristics of the binding pocket of PTP1B, a series of bis-arylethenesulfonic acid ester derivatives were designed and synthesized. These novel molecules, particularly Y-shaped bis-arylethenesulfonic acid ester derivatives, exhibited high PTP1B inhibitory activity, moderate selectivity, and great potential in penetrating cellular membranes (compound 7p, CLogP=9...
March 23, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28366775/noonan-syndrome-associated-shp2-mutation-differentially-modulates-the-expression-of-postsynaptic-receptors-according-to-developmental-maturation
#10
Jun-Young Oh, Sangmyung Rhee, Alcino J Silva, Yong-Seok Lee, Hyong Kyu Kim
Glutamate is the major excitatory neurotransmitter in the central nervous system, and related signaling involves both AMPA and NMDA subtype receptors. The expression of glutamate receptors is dynamically regulated during development. Recent studies showed that the dysregulation of glutamate receptor expression and function is associated with neurodevelopmental disorders including intellectual disability. Previously, a Noonan syndrome (NS)-associated SHP2 mutation (SHP2(D61G)) was shown to increase the synaptic delivery of AMPA receptor, subsequently impairing synaptic plasticity and learning in adult mice...
March 31, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28365441/the-multi-site-docking-protein-gab1-is-constitutively-phosphorylated-independent-from-its-recruitment-to-the-plasma-membrane-in-jak2-v617f-positive-cells-and-mediates-proliferation-of-human-erythroleukaemia-cells
#11
Hannes Bongartz, Wiebke Hessenkemper, Christian Müller, Melissa Fensky, Johannes Fritsch, Katharina Mandel, Iris Behrmann, Claude Haan, Thomas Fischer, Stephan M Feller, Fred Schaper
The constitutively active Janus kinase 2 mutant Jak2-V617F is responsible for cytokine-independent growth of hematopoietic cells and the development of myeloproliferative neoplasms, such as polycythaemia vera and essential thrombocythaemia. Cells expressing Jak2-V617F exhibit constitutive STAT, MAPK, and PI3K signalling, and constitutive association of the multi-site docking protein Gab1 to PIP3 at the plasma membrane. Here, we demonstrate the crucial role of Gab1 for the proliferation of Jak2-V617F-positive human erythroleukaemia (HEL) cells...
March 29, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28352079/protein-tyrosine-phosphatase-shp2-deficiency-in-podocytes-attenuates-lipopolysaccharide-induced-proteinuria
#12
Ming-Fo Hsu, Ahmed Bettaieb, Yoshihiro Ito, James Graham, Peter J Havel, Fawaz G Haj
Podocytes are specialized epithelial cells that play a significant role in maintaining the integrity of the glomerular filtration barrier and preventing urinary protein leakage. We investigated the contribution of protein tyrosine phosphatase Shp2 to lipopolysaccharide (LPS)-induced renal injury. We report increased Shp2 expression in murine kidneys and cultured podocytes following an LPS challenge. To determine the role of podocyte Shp2 in vivo, we generated podocyte-specific Shp2 knockout (pod-Shp2 KO) mice...
March 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28332308/ceacam1-long-isoform-has-opposite-effects-on-the-growth-of-human-mastocytosis-and-medullary-thyroid-carcinoma-cells
#13
Chiyuki Ueshima, Tatsuki R Kataoka, Yusuke Takei, Masahiro Hirata, Akihiko Sugimoto, Mitsuyoshi Hirokawa, Yoshimichi Okayama, Richard S Blumberg, Hironori Haga
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in a number of tumor cell types. The immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing isoforms of this molecule which possess a long cytoplasmic tail (CEACAM1-L) generally play inhibitory roles in cell function by interacting with Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 and/or SHP-2. Src family kinases (SFKs) are also known to bind to and phosphorylate CEACAM1-L isoforms. Here, we report that CEACAM1 was uniquely expressed at high levels in both human neoplastic mast cells (mastocytosis) and medullary thyroid carcinoma cell (MTC) lines, when compared with their expression in nonneoplastic mast cells or nonneoplastic C cells...
April 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28329685/critical-role-for-gab2-in-neuroblastoma-pathogenesis-through-the-promotion-of-shp2-mycn-cooperation
#14
Xiaoling Zhang, Zhiwei Dong, Cheng Zhang, Choong Yong Ung, Shuning He, Ting Tao, Andre M Oliveira, Alexander Meves, Baoan Ji, A Thomas Look, Hu Li, Benjamin G Neel, Shizhen Zhu
Growing evidence suggests a major role for Src-homology-2-domain-containing phosphatase 2 (SHP2/PTPN11) in MYCN-driven high-risk neuroblastoma, although biologic confirmation and a plausible mechanism for this contribution are lacking. Using a zebrafish model of MYCN-overexpressing neuroblastoma, we demonstrate that mutant ptpn11 expression in the adrenal gland analog of MYCN transgenic fish promotes the proliferation of hyperplastic neuroblasts, accelerates neuroblastomagenesis, and increases tumor penetrance...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28328117/noonan-syndrome-ptpn11-mutations-and-brain-tumors-a-clinical-report-and-review-of-the-literature
#15
Aurore Siegfried, Claude Cances, Marie Denuelle, Najat Loukh, Maïté Tauber, Hélène Cavé, Marie-Bernadette Delisle
Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus...
April 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28319894/resolvin-d1-via-prevention-of-ros-mediated-shp2-inactivation-protects-endothelial-adherens-junction-integrity-and-barrier-function
#16
Rima Chattopadhyay, Somasundaram Raghavan, Gadiparthi N Rao
Resolvins are a novel class of lipid mediators that play an important role in the resolution of inflammation, although the underlying mechanisms are not very clear. To explore the anti-inflammatory mechanisms of resolvins, we have studied the effects of resolvin D1 (RvD1) on lipopolysaccharide (LPS)-induced endothelial barrier disruption as it is linked to propagation of inflammation. We found that LPS induces endothelial cell (EC) barrier disruption via xanthine oxidase (XO)-mediated reactive oxygen species (ROS) production, protein tyrosine phosphatase SHP2 inactivation and Fyn-related kinase (Frk) activation leading to tyrosine phosphorylation of α-catenin and VE-cadherin and their dissociation from each other affecting adherens junction (AJ) integrity and thereby increasing endothelial barrier permeability...
March 6, 2017: Redox Biology
https://www.readbyqxmd.com/read/28306669/role-of-shp2-in-hematopoiesis-and-leukemogenesis
#17
Ruchi Pandey, Mallika Saxena, Reuben Kapur
PURPOSE OF REVIEW: SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11 plays an important role in regulating signaling from cell surface receptor tyrosine kinases during normal development as well as oncogenesis. Herein we review recently discovered roles of SHP2 in normal and aberrant hematopoiesis along with novel strategies to target it. RECENT FINDINGS: Cell autonomous role of SHP2 in normal hematopoiesis and leukemogenesis has long been recognized...
March 16, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28301897/key-insights-into-the-protein-tyrosine-phosphatase-ptpn11-shp2-associated-with-noonan-syndrome-and-cancer
#18
EDITORIAL
Marie-Louise Bondeson
No abstract text is available yet for this article.
April 2017: Human Mutation
https://www.readbyqxmd.com/read/28287082/e3-ligase-fbxw7-is-critical-for-rig-i-stabilization-during-antiviral-responses
#19
Yinjing Song, Lihua Lai, Zhenlu Chong, Jia He, Yuanyuan Zhang, Yue Xue, Yiwei Xie, Songchang Chen, Ping Dong, Luoquan Chen, Zhimin Chen, Feng Dai, Xiaopeng Wan, Peng Xiao, Xuetao Cao, Yang Liu, Qingqing Wang
Viruses can escape from host recognition by degradation of RIG-I or interference with the RIG-I signalling to establish persistent infections. However, the mechanisms by which host cells stabilize RIG-I protein for avoiding its degradation are largely unknown. We report here that, upon virus infection, the E3 ubiquitin ligase FBXW7 translocates from the nucleus into the cytoplasm and stabilizes RIG-I. FBXW7 interacts with SHP2 and mediates the degradation and ubiquitination of SHP2, thus disrupting the SHP2/c-Cbl complex, which mediates RIG-I degradation...
March 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28280247/t-cell-costimulatory-receptor-cd28-is-a-primary-target-for-pd-1-mediated-inhibition
#20
Enfu Hui, Jeanne Cheung, Jing Zhu, Xiaolei Su, Marcus J Taylor, Heidi A Wallweber, Dibyendu K Sasmal, Jun Huang, Jeong M Kim, Ira Mellman, Ronald D Vale
Programmed cell death-1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1-recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system...
March 31, 2017: Science
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