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SHP2 cancer

Alain Couvineau, Stéphanie Dayot, Pascal Nicole, Valérie Gratio, Vinciane Rebours, Anne Couvelard, Thierry Voisin
Orexins (OxA and OxB) also termed hypocretins are hypothalamic neuropeptides involved in central nervous system (CNS) to control the sleep/wake process which is mediated by two G protein-coupled receptor subtypes, OX1R, and OX2R. Beside these central effects, orexins also play a role in various peripheral organs such as the intestine, pancreas, adrenal glands, kidney, adipose tissue and reproductive tract.In the past few years, an unexpected anti-tumoral role of orexins mediated by a new signaling pathway involving the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in both orexin receptors subtypes, the recruitment of the phosphotyrosine phosphatase SHP2 and the induction of mitochondrial apoptosis has been elucidated...
2018: Frontiers in Endocrinology
Pedro Torres-Ayuso, John Brognard
<b/> RAS is one of the most frequently altered oncogenes, yet RAS-driven tumors are largely refractory to anticancer therapies. Fedele and colleagues demonstrate that SHP2 inhibitors prevent adaptive MEK inhibitor resistance; therefore, combining MEK and SHP2 inhibitors represents an exciting new therapeutic approach for the treatment of RAS-driven cancers. Cancer Discov; 8(10); 1210-2. ©2018 AACR. See related article by Fedele et al., p. 1237 .
October 2018: Cancer Discovery
Hongting Tang, Zhen Dai, Xuewen Qin, Wenkang Cai, Liming Hu, Yujia Huang, Wenbing Cao, Fan Yang, Chu Wang, Tao Liu
Protein tyrosine phosphatases (PTPs) play critical roles in cell signaling pathways, but identification of unknown PTPs for a given substrate in live cells remain technically challenging. Here, we synthesized a series of tyrosine-based irreversible PTP inhibitors and characterized by site-specific encoding on substrate proteins in cells with an expanded genetic code. By fine-tuning the chemical reactivity, we identified optimal active amino acid probes to covalently cross-link a PTP and its substrate both in vitro and in mammalian cells...
October 17, 2018: Journal of the American Chemical Society
Mihwa Kim, Liza D Morales, Ik-Soon Jang, Yong-Yeon Cho, Dae Joon Kim
The signal transducer and activator of transcription 3 (STAT3) protein is a major transcription factor involved in many cellular processes, such as cell growth and proliferation, differentiation, migration, and cell death or cell apoptosis. It is activated in response to a variety of extracellular stimuli including cytokines and growth factors. The aberrant activation of STAT3 contributes to several human diseases, particularly cancer. Consequently, STAT3-mediated signaling continues to be extensively studied in order to identify potential targets for the development of new and more effective clinical therapeutics...
September 11, 2018: International Journal of Molecular Sciences
Ryouhei Tsutsumi, Hao Ran, Benjamin G Neel
Due to the involvement of SHP2 (SH2 domain-containing protein-tyrosine phosphatase) in human disease, including Noonan syndrome and cancer, several inhibitors targeting SHP2 have been developed. Here, we report that the commonly used SHP2 inhibitor NSC-87877 does not exhibit robust inhibitory effects on growth factor-dependent MAPK (mitogen-activated protein kinase) pathway activation and that the recently developed active site-targeting SHP2 inhibitors IIB-08, 11a-1, and GS-493 show off-target effects on ligand-evoked activation/trans-phosphorylation of the PDGFRβ (platelet-derived growth factor receptor β)...
September 2018: FEBS Open Bio
Ramona Schulz-Heddergott, Nadine Stark, Shelley J Edmunds, Jinyu Li, Lena-Christin Conradi, Hanibal Bohnenberger, Fatih Ceteci, Florian R Greten, Matthias Dobbelstein, Ute M Moll
Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q ) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth...
August 13, 2018: Cancer Cell
Robert J Nichols, Franziska Haderk, Carlos Stahlhut, Christopher J Schulze, Golzar Hemmati, David Wildes, Christos Tzitzilonis, Kasia Mordec, Abby Marquez, Jason Romero, Tientien Hsieh, Aubhishek Zaman, Victor Olivas, Caroline McCoach, Collin M Blakely, Zhengping Wang, Gert Kiss, Elena S Koltun, Adrian L Gill, Mallika Singh, Mark A Goldsmith, Jacqueline A M Smith, Trever G Bivona
Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E -driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C )...
September 2018: Nature Cell Biology
Gabrielle S Wong, Jin Zhou, Jie Bin Liu, Zhong Wu, Xinsen Xu, Tianxia Li, David Xu, Steven E Schumacher, Jens Puschhof, James McFarland, Charles Zou, Austin Dulak, Les Henderson, Peng Xu, Emily O'Day, Rachel Rendak, Wei-Li Liao, Fabiola Cecchi, Todd Hembrough, Sarit Schwartz, Christopher Szeto, Anil K Rustgi, Kwok-Kin Wong, J Alan Diehl, Karin Jensen, Francesco Graziano, Annamaria Ruzzo, Shaunt Fereshetian, Philipp Mertins, Steven A Carr, Rameen Beroukhim, Kenichi Nakamura, Eiji Oki, Masayuki Watanabe, Hideo Baba, Yu Imamura, Daniel Catenacci, Adam J Bass
In the Supplementary Information originally published with this article, a lane was missing in the β-actin blot in Supplementary Fig. 2. The lane has been added. The error has been corrected in the Supplementary Information associated with this article.
August 9, 2018: Nature Medicine
Carmine Fedele, Hao Ran, Brian Diskin, Wei Wei, Jayu Jen, Mitchell J Geer, Kiyomi Araki, Ugur Ozerdem, Diane M Simeone, George Miller, Benjamin G Neel, Kwan Ho Tang
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 ( PTPN11 ) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target...
October 2018: Cancer Discovery
Yuncang Yuan, Guoxiang Qi, Hao Shen, Aizhen Guo, Fuao Cao, Yan Zhu, Chunjie Xiao, Wenjun Chang, Shangyong Zheng
In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In this study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors...
July 10, 2018: International Journal of Cancer. Journal International du Cancer
Chen Kan, Fan Yang, Siying Wang
Stem cells, including embryonic stem cells (ESCs) and adult stem cells, play a central role in mammal organism development and homeostasis. They have two unique properties: the capacity for self-renewal and the ability to differentiate into many specialized cell types. Src homology region 2- (SH2-) containing protein tyrosine phosphatase 2 (SHP-2), a nonreceptor protein tyrosine phosphatase encoded by protein tyrosine phosphatase nonreceptor type 11 gene (PTPN11), regulates multicellular differentiation, proliferation, and survival through numerous conserved signal pathways...
2018: Stem Cells International
Jun Cao, Yu-Qing Huang, Jiao-Sun, Xia-Bin Lan, Ming-Hua Ge
Some thyroid carcinomas (TCs) have a violent biological behavior and poor prognosis, and lacking of effective molecular markers is still the main obstacle for clinical stratified diagnosis and treatment of TC. The aim of the study was to discover the clinicopathological and prognostic implications of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) and Hook microtubule tethering protein 1(Hook1) expression in TC. The expression of SHP2 and Hook1was detected by immunohistochemistry on tissue microarrays from 313 primary TC who underwent surgery during January 2006 and January 2010 in Zhejiang Cancer Hospital...
June 25, 2018: Human Pathology
Cijo George Vazhappilly, Ekram Saleh, Wafaa Ramadan, Varsha Menon, Aya Mudhafar Al-Azawi, Hamadeh Tarazi, Hajjaj Abdu-Allah, Abdel-Nasser El-Shorbagi, Raafat El-Awady
Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate-4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2...
June 27, 2018: Investigational New Drugs
Mathurin Dorel, Bertram Klinger, Torsten Gross, Anja Sieber, Anirudh Prahallad, Evert Bosdriesz, Lodewyk Wessels, Nils Blüthgen
Motivation: Intracellular signalling is realised by complex signalling networks which are almost impossible to understand without network models, especially if feedbacks are involved. Modular Response Analysis (MRA) is a convenient modelling method to study signalling networks in various contexts. Results: We developed the software package STASNet that provides an augmented and extended version of MRA suited to model signalling networks from incomplete perturbation schemes and multi-perturbation data...
June 19, 2018: Bioinformatics
Chuan Chen, Tongdan Xue, Peng Fan, Linlin Meng, Jingjing Wei, Duqiang Luo
Fumosorinone (Fumos) isolated from entomogenous fungi Isaria fumosorosea exhibited selective inhibition of Src homology phosphotyrosine phosphatase 2 inhibitor (Shp2) in our previous study. The purpose of the present study was to investigate the effects of Fumos on cell cycle arrest, tumor cell migration and the in vitro antiproliferative activity of Fumos alone or in combination with the commonly used cytotoxic drugs 5-fluoracil (5-FU) and p38 inhibitor SB203580. Fumos exhibited cytotoxicity against selected human cancel lines, including HeLa, MDA-MB-231 and MDA-MB-453 cell lines...
June 2018: Oncology Letters
Diana F Rojas-Rengifo, Maria Camila Alvarez-Silva, Cindy P Ulloa-Guerrero, Vanessa Lucía Nuñez-Velez, Maria Del Pilar Delgado, Sonia Milena Aguilera, Harold Castro, Carlos Alberto Jaramillo, Andrés Fernando González Barrios
The Helicobacter pylori cytotoxin-associated gene A (CagA) is known for causing gastroduodenal diseases, such as atrophic gastritis and peptic ulcerations. Furthermore Helicobacter pylori CagA positive strains has been reported as one of the main risk factors for gastric cancer (Parsonnet et al., 1997). Structural variations in the CagA structure can alter its affinity with the host proteins, inducing differences in the pathogenicity of H. pylori. CagA N-terminal region is characterized for be conserved among all H...
October 2018: Computational Biology and Chemistry
Gabrielle S Wong, Jin Zhou, Jie Bin Liu, Zhong Wu, Xinsen Xu, Tianxia Li, David Xu, Steven E Schumacher, Jens Puschhof, James McFarland, Charles Zou, Austin Dulak, Les Henderson, Peng Xu, Emily O'Day, Rachel Rendak, Wei-Li Liao, Fabiola Cecchi, Todd Hembrough, Sarit Schwartz, Christopher Szeto, Anil K Rustgi, Kwok-Kin Wong, J Alan Diehl, Karin Jensen, Francesco Graziano, Annamaria Ruzzo, Shaunt Fereshetian, Philipp Mertins, Steven A Carr, Rameen Beroukhim, Kenichi Nakamura, Eiji Oki, Masayuki Watanabe, Hideo Baba, Yu Imamura, Daniel Catenacci, Adam J Bass
The role of KRAS, when activated through canonical mutations, has been well established in cancer1 . Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas2-4 . KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels...
July 2018: Nature Medicine
Dietrich A Ruess, Guus J Heynen, Katrin J Ciecielski, Jiaoyu Ai, Alexandra Berninger, Derya Kabacaoglu, Kivanc Görgülü, Zahra Dantes, Sonja M Wörmann, Kalliope N Diakopoulos, Angeliki F Karpathaki, Marlena Kowalska, Ezgi Kaya-Aksoy, Liang Song, Eveline A Zeeuw van der Laan, María P López-Alberca, Marc Nazaré, Maximilian Reichert, Dieter Saur, Mert M Erkan, Ulrich T Hopt, Bruno Sainz, Walter Birchmeier, Roland M Schmid, Marina Lesina, Hana Algül
The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors1 . Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1-7 . Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro8 ...
July 2018: Nature Medicine
Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, Giovanni Germano, Astrid Bosma, Paul Krimpenfort, Cor Lieftink, Jeffrey D Steinberg, Niels de Wit, Samuel Gonçalves-Ribeiro, Ernest Nadal, Alberto Bardelli, Alberto Villanueva, Rene Bernards
RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3 . Inhibition of the RAS oncoproteins has proven difficult4 , and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms8 . It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10 ...
July 2018: Nature Medicine
Sumit Bhattacharyya, Leo Feferman, Xiaorui Han, Yilan Ouyang, Fuming Zhang, Robert J Linhardt, Joanne K Tobacman
Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to be up-regulated when arylsulfatase B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously been reported to inhibit the activity of the ubiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism by which decline in ARSB leads to decline in SHP2 activity is unclear...
July 13, 2018: Journal of Biological Chemistry
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