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https://read.qxmd.com/read/30755818/synergistic-effects-of-shp2-and-pi3k-pathway-inhibitors-in-gab2-overexpressing-ovarian-cancer
#1
Bowen Sun, Nathaniel R Jensen, Dongjun Chung, Meixiang Yang, Amanda C LaRue, Hiu Wing Cheung, Qi Wang
The scaffold/adaptor growth factor receptor bound 2 (GRB2)-associated binding protein 2 (GAB2) is frequently amplified and/or overexpressed in primary high-grade serous ovarian cancers (HGSOCs). Here we investigate a novel treatment strategy by targeting SHP2 and PI3K signaling in HGSOCs with GAB2 amplification/overexpression (GAB2High ). The expression of GAB2 was analyzed in primary HGSOCs and ovarian cancer cell lines. In vitro and in vivo assays were performed to demonstrate the effect of SHP2 and PI3K-mediated GAB2High HGSOC progression...
2019: American Journal of Cancer Research
https://read.qxmd.com/read/30696956/src-and-shp2-coordinately-regulate-the-dynamics-and-organization-of-vimentin-filaments-during-cell-migration
#2
Cheng-Yi Yang, Po-Wei Chang, Wen-Hsin Hsu, Hsuan-Chia Chang, Chien-Lin Chen, Chien-Chen Lai, Wen-Tai Chiu, Hong-Chen Chen
Vimentin intermediate filaments (VIFs), expressed in most mesenchymal and cancer cells, undergo dramatic reorganization during cell migration; however, the mechanism remains obscure. This study demonstrates that upon growth-factor stimulation, Src directly phosphorylates vimentin at Tyr117, leading to VIF disassembly into squiggles and particles at the cell edge during lamellipodia formation. The protein tyrosine phosphatase SHP2 counteracted the Src effects on VIF tyrosine phosphorylation and organization...
January 29, 2019: Oncogene
https://read.qxmd.com/read/30688459/6-amino-3-methylpyrimidinones-as-potent-selective-and-orally-efficacious-shp2-inhibitors
#3
Patrick Sarver, Michael G Acker, Jeffrey Bagdanoff, Zhuoliang Chen, Ying-Nan P Chen, Homan Chan, Brant Firestone, Michelle Fodor, Jorge Fortanet, Huaixiang Hao, Murphy Hentemann, Mitsunori Kato, Robert Koenig, Laura R LaBonte, Gang Liu, Shumei Liu, Chen Liu, Eric McNeill, Morvarid Mohseni, Martin Sendzik, Travis Stams, Stan Spence, Victoriano Tamez, Ritesh Tichkule, Christopher S Towler, Hongyun Wang, Ping Wang, Sarah L Williams, Bing Yu, Matthew J LaMarche
Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator due to its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this second manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design...
January 28, 2019: Journal of Medicinal Chemistry
https://read.qxmd.com/read/30685130/association-of-nuclear-localization-of-shp2-and-yap1-with-unfavorable-prognosis-in-non-small-cell-lung-cancer
#4
Ming-Jenn Chen, Yao-Chen Wang, De-Wei Wu, Chi-Yi Chen, Huei Lee
Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is ubiquitously expressed in cytoplasmic localization, which in turn confers tumor malignancy and poor prognosis in various human cancers. YAP1 interacts with SHP2 to promote translocation of SHP2 to nucleus, which consequently promotes Wnt target activation. However, the oncogenic role of the nuclear localization of SHP2 in human cancers remains unclear. We hypothesized that nuclear SHP2 localization, in combination with nuclear YAP1 expression, could be associated with poor overall survival (OS) and relapse free survival (RFS) due to an increase in cyclin D1 and c-Myc mRNA expression following activation of Wnt/ß-catenin signaling...
January 18, 2019: Pathology, Research and Practice
https://read.qxmd.com/read/30644389/tyrosyl-phosphorylation-of-kras-stalls-gtpase-cycle-via-alteration-of-switch-i-and-ii-conformation
#5
Yoshihito Kano, Teklab Gebregiworgis, Christopher B Marshall, Nikolina Radulovich, Betty P K Poon, Jonathan St-Germain, Jonathan D Cook, Ivette Valencia-Sama, Benjamin M M Grant, Silvia Gabriela Herrera, Jinmin Miao, Brian Raught, Meredith S Irwin, Jeffrey E Lee, Jen Jen Yeh, Zhong-Yin Zhang, Ming-Sound Tsao, Mitsuhiko Ikura, Michael Ohh
Deregulation of the RAS GTPase cycle due to mutations in the three RAS genes is commonly associated with cancer development. Protein tyrosine phosphatase SHP2 promotes RAF-to-MAPK signaling pathway and is an essential factor in RAS-driven oncogenesis. Despite the emergence of SHP2 inhibitors for the treatment of cancers harbouring mutant KRAS, the mechanism underlying SHP2 activation of KRAS signaling remains unclear. Here we report tyrosyl-phosphorylation of endogenous RAS and demonstrate that KRAS phosphorylation via Src on Tyr32 and Tyr64 alters the conformation of switch I and II regions, which stalls multiple steps of the GTPase cycle and impairs binding to effectors...
January 15, 2019: Nature Communications
https://read.qxmd.com/read/30584278/synthesis-of-small-peptide-compounds-molecular-docking-and-inhibitory-activity-evaluation-against-phosphatases-ptp1b-and-shp2
#6
Tomasz Kostrzewa, Kamlesh K Sahu, Magdalena Gorska-Ponikowska, Jack A Tuszynski, Alicja Kuban-Jankowska
Background: The protein tyrosine phosphatases PTP1B and SHP2 are promising drug targets in treatment design for breast cancer. Searching for specific inhibitors of their activity has recently become the challenge of many studies. Previous work has indicated that the promising PTP inhibitors may be small compounds that are able to bind and interact with amino residues from the binding site. Purpose: The main goal of our study was to synthesize and analyze the effect of selected small peptide inhibitors on oncogenic PTP1B and SHP2 enzymatic activity and viability of MCF7 breast cancer cells...
2018: Drug Design, Development and Therapy
https://read.qxmd.com/read/30553753/ilk-and-shp2-expression-identify-a-poor-prognostic-cohort-of-egfr-mutant-lung-cancer
#7
Carminia Maria Della Corte, Carl Michael Gay, Lauren Averett Byers, Floriana Morgillo
No abstract text is available yet for this article.
December 12, 2018: EBioMedicine
https://read.qxmd.com/read/30526882/inhibition-of-inflammatory-signaling-in-tet2-mutant-preleukemic-cells-mitigates-stress-induced-abnormalities-and-clonal-hematopoiesis
#8
Zhigang Cai, Jonathan J Kotzin, Baskar Ramdas, Sisi Chen, Sai Nelanuthala, Lakshmi Reddy Palam, Ruchi Pandey, Raghuveer Singh Mali, Yan Liu, Mark R Kelley, George Sandusky, Morvarid Mohseni, Adam Williams, Jorge Henao-Mejia, Reuben Kapur
Inflammation is a risk factor for cancer development. Individuals with preleukemic TET2 mutations manifest clonal hematopoiesis and are at a higher risk of developing leukemia. How inflammatory signals influence the survival of preleukemic hematopoietic stem and progenitor cells (HSPCs) is unclear. We show a rapid increase in the frequency and absolute number of Tet2-KO mature myeloid cells and HSPCs in response to inflammatory stress, which results in enhanced production of inflammatory cytokines, including interleukin-6 (IL-6), and resistance to apoptosis...
December 6, 2018: Cell Stem Cell
https://read.qxmd.com/read/30473379/integrin-linked-kinase-ilk-and-src-homology-2-domain-containing-phosphatase-2-shp2-novel-targets-in-egfr-mutation-positive-non-small-cell-lung-cancer-nsclc
#9
Niki Karachaliou, Andres Felipe Cardona, Jillian Wilhelmina Paulina Bracht, Erika Aldeguer, Ana Drozdowskyj, Manuel Fernandez-Bruno, Imane Chaib, Jordi Berenguer, Mariacarmela Santarpia, Masaoki Ito, Jordi Codony-Servat, Rafael Rosell
BACKGROUND: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation...
November 22, 2018: EBioMedicine
https://read.qxmd.com/read/30467378/conditional-knockout-of-shp2-in-erbb2-transgenic-mice-or-inhibition-in-her2-amplified-breast-cancer-cell-lines-blocks-oncogene-expression-and-tumorigenesis
#10
Hua Zhao, Elisha Martin, Fatimah Matalkah, Neal Shah, Alexey Ivanov, J Michael Ruppert, Paul R Lockman, Yehenew M Agazie
Overexpression of the human epidermal growth factor receptor 2 (HER2) is the cause of HER2-positive breast cancer (BC). Although HER2-inactivating therapies have benefited BC patients, development of resistance and disease recurrence have been the major clinical problems, pointing to a need for alternative therapeutic strategies. For that to happen, proteins that play critical roles in the biology of HER2-induced tumorigenesis have to be identified and characterized. Here, we show that the Src homology phosphotyrosyl phosphatase 2 (Shp2) encoded by the Ptpn11 gene is a requisite for ErbB2-induced tumorigenesis...
November 22, 2018: Oncogene
https://read.qxmd.com/read/30461272/total-synthesis-biological-evaluation-and-target-identification-of-rare-abies-sesquiterpenoids
#11
Dexter C Davis, Dominic G Hoch, Li Wu, Daniel Abegg, Brandon S Martin, Zhong-Yin Zhang, Alexander Adibekian, Mingji Dai
Abiespiroside A (1), beshanzuenone C (2), and beshanzuenone D (3) belong to the Abies sesquiterpenoid family. Beshanzue-nones C (2) and D (3) are isolated from the critically endangered Chinese fir tree species Abies beshanzuensis and demon-strated weak inhibiting activity against protein tyrosine phosphatase 1B (PTP1B). We describe herein the first total synthe-ses of these Abies sesquiterpenoids relying on the sustainable and inexpensive chiral pool molecule (+)-carvone. The synthe-ses feature a palladium-catalyzed hydrocarbonylative lactonization to install the 6,6-fused bicyclic ring system and a Dreiding-Schmidt reaction to build the oxaspirolactone moiety of these target molecules...
November 21, 2018: Journal of the American Chemical Society
https://read.qxmd.com/read/30430347/probing-the-dynamic-mechanism-of-uncommon-allosteric-inhibitors-optimized-to-enhance-drug-selectivity-of-shp2-with-therapeutic-potential-for-cancer-treatment
#12
Abdolkarim Farrokhzadeh, Farideh Badichi Akher, Mahmoud E S Soliman
There is currently considerable interest in SHP2 as a potential target for treatment of cancer. Mutation in SHP2, particularly the E76A mutation, has been found to seriously confer the phosphatase high activity. Recently, two compounds, 1 and 23, have been reported as potent allosteric inhibitors of both SHP2 wild type (SHP2WT ) and the E76A mutant (SHP2E76A ), with higher activity than other inhibitors. However, the structural and dynamic implications of their inhibitory mechanisms are yet unexplored which deserve further attention...
November 15, 2018: Applied Biochemistry and Biotechnology
https://read.qxmd.com/read/30398108/the-landscape-of-protein-tyrosine-phosphatase-shp2-and-cancer
#13
Ashfaq Ur Rehman, Mueed Ur Rehman, K M Tahir, Shah Saud, Hao Liu, Dong Song, Pinky Sultana, Abdul Wadood, Hai-Feng Chen
Role of Shp2: The dysregulation of cell signaling cascades associated with the cell differentiation and growth, due to the deletion, insertion or point mutation in specific amino acids which alters the intrinsic conformation of the protein, can ultimately lead to a fatal cancer disease. The protein tyrosine phosphatase has been recognized as a key regulator of extracellular stimuli such as cytokine receptor and receptor tyrosine kinase signaling. In the last era, the PTPN11 gene (encode a Shp2 protein) and its association with acute myeloid, juvenile myelomonocytic, and B-cell acute lymphoblastic leukemia, Noonan syndrome, and myelodysplastic has been recognized, the cause of such deadly disease due to the occurrence of germline mutations in the interface of PTP and SH2 domain...
November 5, 2018: Current Pharmaceutical Design
https://read.qxmd.com/read/30389797/-combination-cancer-immunotherapy-targeting-pd-1-and-gitr-can-rescue-cd8-t-cell-dysfunction-and-maintain-memory-phenotype
#14
Bei Wang, Wen Zhang, Vladimir Jankovic, Jacquelynn Golubov, Patrick Poon, Erin M Oswald, Cagan Gurer, Joyce Wei, Ilyssa Ramos, Qi Wu, Janelle Waite, Min Ni, Christina Adler, Yi Wei, Lynn Macdonald, Tracey Rowlands, Susannah Brydges, Jean Siao, William Poueymirou, Douglas MacDonald, George D Yancopoulos, Matthew A Sleeman, Andrew J Murphy, Dimitris Skokos
Most patients with cancer do not develop durable antitumor responses after programmed cell death protein 1 (PD-1) or programmed cell death ligand 1(PD-L1) checkpoint inhibition monotherapy because of an ephemeral reversal of T cell dysfunction and failure to promote long-lasting immunological T cell memory. Activating costimulatory pathways to induce stronger T cell activation may improve the efficacy of checkpoint inhibition and lead to durable antitumor responses. We performed single-cell RNA sequencing of more than 2000 tumor-infiltrating CD8+ T cells in mice receiving both PD-1 and GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) antibodies and found that this combination synergistically enhanced the effector function of expanded CD8+ T cells by restoring the balance of key homeostatic regulators CD226 and T cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to a robust survival benefit...
November 2, 2018: Science Immunology
https://read.qxmd.com/read/30375388/structural-reorganization-of-shp2-by-oncogenic-mutations-and-implications-for-oncoprotein-resistance-to-allosteric-inhibition
#15
Jonathan R LaRochelle, Michelle Fodor, Vidyasiri Vemulapalli, Morvarid Mohseni, Ping Wang, Travis Stams, Matthew J LaMarche, Rajiv Chopra, Michael G Acker, Stephen C Blacklow
Activating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099...
October 30, 2018: Nature Communications
https://read.qxmd.com/read/30375376/mechanism-of-activating-mutations-and-allosteric-drug-inhibition-of-the-phosphatase-shp2
#16
Ricardo A P Pádua, Yizhi Sun, Ingrid Marko, Warintra Pitsawong, John B Stiller, Renee Otten, Dorothee Kern
Protein tyrosine phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations...
October 30, 2018: Nature Communications
https://read.qxmd.com/read/30374120/evaluating-the-origin-and-virulence-of-a-helicobacter-pylori-caga-positive-strain-isolated-from-a-non-human-primate
#17
Kana Hashi, Chihiro Imai, Koji Yahara, Kamrunnesa Tahmina, Takeru Hayashi, Takeshi Azuma, Takako Miyabe-Nishiwaki, Hideyuki Sato, Masao Matsuoka, Sachi Niimi, Munehiro Okamoto, Masanori Hatakeyama
Helicobacter pylori cagA-positive strains are critically involved in the development of gastric cancer. Upon delivery into gastric epithelial cells via type IV secretion, the cagA-encoded CagA interacts with and thereby perturbs the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1b via the tyrosine-phosphorylated EPIYA-C/D segment and the CM sequence, respectively. Importantly, sequences spanning these binding regions exhibit variations among CagA proteins, which influence the pathobiological/oncogenic potential of individual CagA...
October 29, 2018: Scientific Reports
https://read.qxmd.com/read/30355677/ptpn11-plays-oncogenic-roles-and-is-a-therapeutic-target-for-braf-wild-type-melanomas
#18
Kristen S Hill, Evan R Roberts, Xue Wang, Ellen Marin, Taeeun D Park, Sorany Son, Yuan Ren, Bin Fang, Sean Yoder, Sungjune Kim, Lixin Wan, Amod A Sarnaik, John M Koomen, Jane L Messina, Jamie K Teer, Youngchul Kim, Jie Wu, Charles E Chalfant, Minjung Kim
Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells...
October 24, 2018: Molecular Cancer Research: MCR
https://read.qxmd.com/read/30343889/immune-inhibitory-receptor-lilrb2-is-critical-for-the-endometrial-cancer-progression
#19
Hongfang Shao, Li Ma, Feng Jin, Yang Zhou, Minfang Tao, Yincheng Teng
Although leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is known as an immune inhibitory receptor to suppress the immune system, its function in cancer development remains largely unknown. Herein, we provide the first body of information showing that LILRB2 is highly expressed in the endometrial cancer. More importantly, the expression levels of LILRB2 are inversely correlated with the overall patients' survival. Knockdown of LILRB2 results in a dramatic decrease in the proliferation, colony formation and migration in several endometrial cancer cell lines in vitro...
October 18, 2018: Biochemical and Biophysical Research Communications
https://read.qxmd.com/read/30319552/the-anti-tumoral-properties-of-orexin-hypocretin-hypothalamic-neuropeptides-an-unexpected-therapeutic-role
#20
REVIEW
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
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