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https://www.readbyqxmd.com/read/28074573/structural-functional-and-clinical-characterization-of-a-novel-ptpn11-mutation-cluster-underlying-noonan-syndrome
#1
Luca Pannone, Gianfranco Bocchinfuso, Elisabetta Flex, Cesare Rossi, Giuseppina Baldassarre, Christina Lissewski, Francesca Pantaleoni, Federica Consoli, Francesca Lepri, Monia Magliozzi, Massimiliano Anselmi, Giovanni Sorge, Kadri Karaer, Goran Cuturilo, Alessandro Sartorio, Sigrid Tinschert, Maria Accadia, Maria C Digilio, Giuseppe Zampino, Alessandro De Luca, Hélène Cavé, Martin Zenker, Bruce D Gelb, Bruno Dallapiccola, Lorenzo Stella, Giovanni B Ferrero, Simone Martinelli, Marco Tartaglia
Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu(261) , Leu(262) and Arg(265) in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling...
January 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28059452/shp2-promotes-liver-cancer-stem-cell-expansion-by-augmenting-%C3%AE-catenin-signaling-and-predicts-chemotherapeutic-response-of-patients
#2
Daimin Xiang, Zhuo Cheng, Hui Liu, Xue Wang, Tao Han, Wen Sun, Xiaofeng Li, Wen Yang, Cheng Chen, Mingyang Xia, Na Liu, Shengyong Yin, Guangzhi Jin, Terence Lee, Liwei Dong, Heping Hu, Hongyang Wang, Jin Ding
: Src-homology 2 domain-containing phosphatase 2 (Shp2) has been reported to play an important role in the maintenance and self-renewal of embryonic and adult stem cells, but its role in cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of Shp2 in both chemoresistant hepatocellular carcinomas (HCCs) and recurrent HCCs from patients. A remarkable increase of Shp2 was detected in sorted epithelial cell adhesion molecule-positive or cluster of differentiation 133-positive liver CSCs and in CSC-enriched hepatoma spheroids from patients...
November 5, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28035977/shp2-socs3-and-pias3-expression-patterns-in-medulloblastomas-relevance-to-stat3-activation-and-resveratrol-suppressed-stat3-signaling
#3
Cong Li, Hong Li, Peng Zhang, Li-Jun Yu, Tian-Miao Huang, Xue Song, Qing-You Kong, Jian-Li Dong, Pei-Nan Li, Jia Liu
BACKGROUND: Activated STAT3 signaling is critical for human medulloblastoma cells. SHP2, SOCS3 and PIAS3 are known as the negative regulators of STAT3 signaling, while their relevance to frequent STAT3 activation in medulloblastomas remains unknown. METHODS: Tissue microarrays were constructed with 17 tumor-surrounding noncancerous brain tissues and 61 cases of the classic medulloblastomas, 44 the large-cell medulloblastomas, and 15 nodular medulloblastomas, which were used for immunohistochemical profiling of STAT3, SHP2, SOCS3 and PIAS3 expression patterns and the frequencies of STAT3 nuclear translocation...
December 27, 2016: Nutrients
https://www.readbyqxmd.com/read/28035384/correlative-analyses-of-the-expression-levels-of-pias3-p-shp2-socs1-and-socs3-with-stat3-activation-in-human-astrocytomas
#4
Li-Hong Liu, Hong Li, Xiao-Xin Cheng, Qing-You Kong, Xiao-Yan Chen, Mo-Li Wu, Yan Li, Jia Liu, Cong Li
The importance of signal transducer and activator of transcription 3 (STAT3) signaling in the growth and survival of glioblastoma cells has been well documented, while the reasons leading to STAT3 activation remains to be elucidated. Suppressors of cytokine signaling (SOCS) 1 and SOCS3, SH2 domain‑containing phosphatase (SHP2) and protein inhibitors of activated STAT3 (PIAS3) are known to inhibit STAT3 signal transduction, while their expression statuses in the four grades of astrocytomas and relevance with STAT3 activation remain to be described...
December 28, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27997991/decreased-frequencies-and-impaired-functions-of-the-cd31-subpopulation-in-treg-cells-associated-with-decreased-foxp3-expression-and-enhanced-treg-cell-defects-in-patients-with-coronary-heart-disease
#5
L Huang, Y Zheng, X Yuan, Y Ma, G Xie, W Wang, H Chen, L Shen
Coronary heart disease (CHD) is one of the most common types of organ lesions caused by atherosclerosis, in which CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) ) regulatory T cells (Treg ) play an atheroprotective role. However, Treg cell numbers are decreased and their functions are impaired in atherosclerosis; the underlying mechanisms remain unclear. CD31 plays an important part in T cell response and contributes to maintaining T cell tolerance. The immunomodulatory effects of CD31 are also implicated in atherosclerosis...
November 5, 2016: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/27974211/dual-shp2-and-pten-deficiencies-promote-non-alcoholic-steatohepatitis-and-genesis-of-liver-tumor-initiating-cells
#6
Xiaolin Luo, Rui Liao, Kaisa L Hanley, Helen He Zhu, Kirsten N Malo, Carolyn Hernandez, Xufu Wei, Nissi M Varki, Nazilla Alderson, Catherine Chu, Shuangwei Li, Jia Fan, Rohit Loomba, Shuang-Jian Qiu, Gen-Sheng Feng
The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation and elevated ROS and inflammation in the hepatic microenvironment...
December 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27959415/promoter-methylation-attenuates-shp1-expression-and-function-in-patients-with-primary-central-nervous-system-lymphoma
#7
Jing Liu, Yaming Wang, Xuefei Sun, Nan Ji, Shengjun Sun, Yajie Wang, Fusheng Liu, Qu Cui, Chen Wang, Yuanbo Liu
The Src homology region 2 domain-containing phosphatase-1 (SHP1) is a critical negative regulator involved in the JAK/STAT signaling pathway. The SHP1 gene has been proposed as a candidate tumor suppressor in solid and hematological malignancies and promoter methylation is an important biological process in controlling tumorigenesis. However, the detailed roles of SHP1 promoter methylation in the pathogenesis of primary central nervous system lymphoma (PCNSL) is largely unknown. In the present study, we evaluated the correlation between SHP1 expression and promoter methylation in patients with PCNSL...
December 8, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27942593/low-dose-dasatinib-rescues-cardiac-function-in-noonan-syndrome
#8
Jae-Sung Yi, Yan Huang, Andrea T Kwaczala, Ivana Y Kuo, Barbara E Ehrlich, Stuart G Campbell, Frank J Giordano, Anton M Bennett
Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the PTPN11 gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS. Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases...
December 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27939989/identification-of-demethylincisterol-a3-as-a-selective-inhibitor-of-protein-tyrosine-phosphatase-shp2
#9
Chuan Chen, Fan Liang, Bo Chen, Zhongyi Sun, Tongdan Xue, Runlei Yang, Duqiang Luo
Shp2 is a classical non-receptor protein tyrosine phosphatase (PTP) involved in many human diseases such as Noonan syndrome and tumors, and identified as a potential therapeutic target. In order to find a potent and selective Shp2 inhibitor, we screened a diverse collection of the secondary metabolites from endophyte fungi using an in vitro enzyme assay, and finally identified a potent Shp2 inhibitor, HLP46 (demethylincisterol A3) from Pestalotiopsis sp. HLP46 was reported to have anti-tumor and anti-inflammation activity previously...
December 8, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27935860/t-lymphocyte-shp2-deficiency-triggers-anti-tumor-immunity-to-inhibit-colitis-associated-cancer-in-mice
#10
Wen Liu, Wenjie Guo, Lihong Shen, Zhen Chen, Qiong Luo, Xiaolin Luo, Gen-Sheng Feng, Yongqian Shu, Yanhong Gu, Qiang Xu, Yang Sun
Nonresolving inflammation is involved in the initiation and progression process of tumorigenesis. Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is known to inhibit acute inflammation but its role in chronic inflammation-associated cancer remains unclear. The role of SHP2 in T cells in dextran sulfate sodium (DSS)-induced colitis and azoxymethane-DSS-induced colitis-associated carcinogenesis was examined using SHP2CD4-/- conditional knockout mice. SHP2 deficiency in T cells aggravated colitis with increased level of pro-inflammatory cytokines including IFN-γ and IL-17A...
December 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27926479/decline-in-arylsulfatase-b-leads-to-increased-invasiveness-of-melanoma-cells
#11
Sumit Bhattacharyya, Leo Feferman, Kaoru Terai, Arkadiusz Z Dudek, Joanne K Tobacman
Arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) is reduced in several malignancies, but levels in melanoma have not been investigated previously. Experiments were performed in melanoma cell lines to determine ARSB activity and impact on melanoma invasiveness. ARSB activity was reduced ~50% in melanoma cells compared to normal melanocytes. Silencing ARSB significantly increased the mRNA expression of chondroitin sulfate proteoglycan(CSPG)4 and pro-matrix metalloproteinase(MMP)-2, known mediators of melanoma progression...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27894814/tanshinone-iia-induced-cell-death-via-mir30b-p53-ptpn11-shp2-signaling-pathway-in-human-hepatocellular-carcinoma-cells
#12
Xuanqi Ren, Cui Wang, Binbin Xie, Linfeng Hu, Hui Chai, Lei Ding, Lihua Tang, Yongliang Xia, Xiaobing Dou
Tanshinone IIA, a multi-pharmaceutical compound from traditional Chinese herb, has been reported to have anti-hepatocarcinomic (HCC) properties through cell death induction. Apart from the typical p53-dependent pathway, mechanisms of the anti-carcinogenic role of Tanshinone remain scarce. In an effort to explore the mechanism behind Tanshinone IIA, we detected the upstream of the p53 and the potential novel pathway. Tanshinone IIA dose-dependently initiated HepG2 cell apoptosis and cell cycle arrest at the G1 checkpoint...
November 25, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27876799/irs4-induces-mammary-tumorigenesis-and-confers-resistance-to-her2-targeted-therapy-through-constitutive-pi3k-akt-pathway-hyperactivation
#13
Gerjon J Ikink, Mandy Boer, Elvira R M Bakker, John Hilkens
In search of oncogenic drivers and mechanisms affecting therapy resistance in breast cancer, we identified Irs4, a poorly studied member of the insulin receptor substrate (IRS) family, as a mammary oncogene by insertional mutagenesis. Whereas normally silent in the postnatal mammary gland, IRS4 is found to be highly expressed in a subset of breast cancers. We show that Irs4 expression in mammary epithelial cells induces constitutive PI3K/AKT pathway hyperactivation, insulin/IGF1-independent cell proliferation, anchorage-independent growth and in vivo tumorigenesis...
November 23, 2016: Nature Communications
https://www.readbyqxmd.com/read/27864293/expressions-of-the-caga-protein-and-caga-signaling-molecules-predict-h-pylori-dependence-of-early-stage-gastric-dlbcl
#14
Sung-Hsin Kuo, Li-Tzong Chen, Chung-Wu Lin, Kun-Huei Yeh, Chia-Tung Shun, Yi-Shin Tzeng, Jyh-Ming Liou, Ming-Shiang Wu, Ping-Ning Hsu, Ann-Lii Cheng
We previously reported that early-stage gastric diffuse large B-cell lymphomas (DLBCLs), including DLBCLs with (DLBCL[MALT]) and without ('pure' DLBCL) the features of MALT lymphomas, can achieve long-term complete remission after frontline Helicobacter pylori (HP) eradication (HPE). We recently reported that expression of CagA and CagA-signaling molecules (p-SHP2 and p-ERK) is associated with the HP-dependence of gastric MALT lymphoma. However, the significance of CagA and CagA-signaling molecules in gastric DLBCL remains unexplored...
November 18, 2016: Blood
https://www.readbyqxmd.com/read/27856613/dorsal-horn-interneuron-derived-netrin-4-contributes-to-spinal-sensitization-in-chronic-pain-via-unc5b
#15
Yasufumi Hayano, Keiko Takasu, Yoshihisa Koyama, Moe Yamada, Koichi Ogawa, Kazuhisa Minami, Toshiyuki Asaki, Kazuhiro Kitada, Satoshi Kuwabara, Toshihide Yamashita
Because of the incomplete understanding of the molecular mechanisms that underlie chronic pain, the currently available treatments for this type of pain remain inefficient. In this study, we show that Netrin-4, a member of the axon guidance molecule family, was expressed in dorsal horn inner lamina II excitatory interneurons in the rat spinal cord. A similar expression pattern for Netrin-4 was also observed in human spinal cord. Behavioral analysis revealed that tactile and heat hyperalgesia after peripheral nerve injury or inflammation were abolished in Netrin-4-mutant rats...
December 12, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27851976/shp1-regulates-bone-mass-by-directing-mesenchymal-stem-cell-differentiation
#16
Menghui Jiang, Chunxing Zheng, Peishun Shou, Na Li, Gang Cao, Qing Chen, Chunliang Xu, Liming Du, Qian Yang, Jianchang Cao, Yanyan Han, Fengying Li, Wei Cao, Feng Liu, Arnold B Rabson, Arthur I Roberts, Weifen Xie, Ying Wang, Yufang Shi
No abstract text is available yet for this article.
November 15, 2016: Cell Reports
https://www.readbyqxmd.com/read/27831560/manipulating-the-air-filled-zebrafish-swim-bladder-as-a-neutrophilic-inflammation-model-for-acute-lung-injury
#17
Yuefei Zhang, Hongcui Liu, Junlin Yao, Yanfeng Huang, Shenlu Qin, Zheng Sun, Yingchun Xu, Shu Wan, Hongqiang Cheng, Chunqi Li, Xue Zhang, Yuehai Ke
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases that are associated with high mortality rates due to treatment limitations. Neutrophils play key roles in the pathogenesis of ALI/ARDS by promoting the inflammation and injury of the alveolar microenvironment. To date, in vivo functional approaches have been limited by the inaccessibility to the alveolar sacs, which are located at the anatomical terminal of the respiratory duct in mammals...
November 10, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27822318/discovery-and-replication-of-a-peripheral-tissue-dna-methylation-biosignature-to-augment-a-suicide-prediction-model
#18
Makena L Clive, Marco P Boks, Christiaan H Vinkers, Lauren M Osborne, Jennifer L Payne, Kerry J Ressler, Alicia K Smith, Holly C Wilcox, Zachary Kaminsky
BACKGROUND: Suicide is the second leading cause of death among adolescents in the USA, and rates are rising. Methods to identify individuals at risk are essential for implementing prevention strategies, and the development of a biomarker can potentially improve prediction of suicidal behaviors. Prediction of our previously reported SKA2 biomarker for suicide and PTSD is substantially improved by questionnaires assessing perceived stress or anxiety and is therefore reliant on psychological assessment...
2016: Clinical Epigenetics
https://www.readbyqxmd.com/read/27803106/egfl6-regulates-the-asymmetric-division-maintenance-and-metastasis-of-aldh-ovarian-cancer-cells
#19
Shoumei Bai, Patrick Ingram, Yu-Chih Chen, Ning Deng, Alex Pearson, Yashar Niknafs, Patrick O'Hayer, Yun Wang, Zhong-Yin Zhang, Elisa Boscolo, Joyce Bischoff, Euisik Yoon, Ronald J Buckanovich
Little is known about the factors that regulate the asymmetric division of cancer stem-like cells (CSC). Here, we demonstrate that EGFL6, a stem cell regulatory factor expressed in ovarian tumor cells and vasculature, regulates ALDH(+) ovarian CSC. EGFL6 signaled at least in part via the oncoprotein SHP2 with concomitant activation of ERK. EGFL6 signaling promoted the migration and asymmetric division of ALDH(+) ovarian CSC. As such, EGFL6 increased not only tumor growth but also metastasis. Silencing of EGFL6 or SHP2 limited numbers of ALDH(+) cells and reduced tumor growth, supporting a critical role for EGFL6/SHP2 in ALDH(+) cell maintenance...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27799550/targeting-of-ras-mediated-fgf-signaling-suppresses-pten-deficient-skin-tumor
#20
Grinu Mathew, Abdul Hannan, Kristina Hertzler-Schaefer, Fen Wang, Gen-Sheng Feng, Jian Zhong, Jean J Zhao, Julian Downward, Xin Zhang
Deficiency in PTEN (phosphatase and tensin homolog deleted on chromosome 10) is the underlying cause of PTEN hamartoma tumor syndrome and a wide variety of human cancers. In skin epidermis, we have previously identified an autocrine FGF signaling induced by loss of Pten in keratinocytes. In this study, we demonstrate that skin hyperplasia requires FGF receptor adaptor protein Frs2α and tyrosine phosphatase Shp2, two upstream regulators of Ras signaling. Although the PI3-kinase regulatory subunits p85α and p85β are dispensable, the PI3-kinase catalytic subunit p110α requires interaction with Ras to promote hyperplasia in Pten-deficient skin, thus demonstrating an important cross-talk between Ras and PI3K pathways...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
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