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https://www.readbyqxmd.com/read/28096188/erk1-2-phosphorylate-gab2-to-promote-a-negative-feedback-loop-that-attenuates-pi3k-akt-signaling
#1
Xiaocui Zhang, Geneviève Lavoie, Antoine Méant, Léo Aubert, Marie Cargnello, André Haman, Trang Hoang, Philippe P Roux
The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells as it is required for PI3K (phosphoinositide 3-kinase) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function...
January 17, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28087344/up-regulation-of-the-active-form-of-small-gtpase-rab13-promotes-macroautophagy-in-vascular-endothelial-cells
#2
Lu Zhang, Fang Dai, LiuQing Cui, Bo Zhou, YuQi Guo
The importance of macroautophagy (hereafter referred to as autophagy) in vascular endothelial cell (VEC) biology and dysfunction is increasingly recognized, but the molecular mechanisms of autophagy in VECs in the presence of serum are still poorly understood. Previously, we identified pterostilbene as a potent autophagy inducer of VECs in the presence of serum. In this study, we used pterostilbene as a tool to induce VEC autophagy and identified the differentially expressed genes using high-throughput DAN microarray...
January 10, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28065675/altered-expression-of-irs2-and-grb2-in-demyelination-of-peripheral-neurons-implications-in-diabetic-neuropathy
#3
Mallahalli S Manu, Kuruvanthe S Rachana, Gopal M Advirao
Demyelination of the peripheral nerves and dysfunction of Schwann cells (SCs) are the chronic complications involved in the development of peripheral neuropathy among diabetic patients. Insulin signaling plays an important role in restoring the myelin proteins in diabetic peripheral neuropathy (DPN). Since insulin levels are altered in diabetes, it becomes of great interest to appreciate the role and regulation of docking and adaptor protein, how these proteins respond to variations in the levels of insulin as experienced in juvenile diabetes...
December 29, 2016: Neuropeptides
https://www.readbyqxmd.com/read/28063625/regulation-of-insulin-receptor-phosphorylation-in-the-brains-of-prenatally-stressed-rats-new-insight-into-the-benefits-of-antidepressant-drug-treatment
#4
Katarzyna Głombik, Joanna Ślusarczyk, Ewa Trojan, Katarzyna Chamera, Bogusława Budziszewska, Władysław Lasoń, Agnieszka Basta-Kaim
A growing body of evidence supports the involvement of disturbances in the brain insulin pathway in the pathogenesis of depression. On the other hand, data concerning the impact of antidepressant drug therapy on brain insulin signaling remain scare and insufficient. We determinated the influence of chronic treatment with antidepressant drugs (imipramine, fluoxetine and tianeptine) on the insulin signaling pathway of the brain of adult prenatally stressed rats. 3-month-old prenatally stressed and control rats were treated for 21 days with imipramine, fluoxetine or tianeptine (10mg/kg/day i...
January 4, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28060514/targeted-covalent-inhibition-of-grb2-sos1-interaction-through-proximity-induced-conjugation-in-breast-cancer-cells
#5
Yongsheng Yu, Yunyu Nie, Qian Feng, Jiale Qu, Rui Wang, Liming Bian, Jiang Xia
Targeted covalent inhibitors of protein-protein interactions differ from reversible inhibitors in that the former bind and covalently bond the target protein at a specific site of the target. The site specificity is the result of the proximity of two reactive groups at the bound state, for example one mild electrophile in the inhibitor and a natural cysteine in the target close to the ligand binding site. Only a few pharmaceutically relevant proteins have this structural feature. Grb2, a key adaptor protein in maintaining the ERK activity via binding Sos1 to activated RTKs, is one: the N-terminal SH3 domain of Grb2 (Grb2N-SH3) carries a unique solvent-accessible cysteine Cys32 close to its Sos1-binding site...
January 6, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28046066/htlv-1-bzip-factor-enhances-t-cell-proliferation-by-impeding-the-suppressive-signaling-of-co-inhibitory-receptors
#6
Haruka Kinosada, Jun-Ichirou Yasunaga, Kazuya Shimura, Paola Miyazato, Chiho Onishi, Tomonori Iyoda, Kayo Inaba, Masao Matsuoka
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. To enhance cell-to-cell transmission of HTLV-1, the virus increases the number of infected cells in vivo. HTLV-1 bZIP factor (HBZ) is constitutively expressed in HTLV-1 infected cells and ATL cells and promotes T-cell proliferation. However, the detailed mechanism by which it does so remains unknown. Here, we show that HBZ enhances the proliferation of expressing T cells after stimulation via the T-cell receptor...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28032751/synthesis-of-grb2-sh2-domain-proteins-for-mirror-image-screening-systems
#7
Taro Noguchi, Hiroyuki Ishiba, Kaori Honda, Yasumitsu Kondoh, Hiroyuki Osada, Hiroaki Ohno, Nobutaka Fujii, Shinya Oishi
Grb2 is an adaptor protein that mediates cellular signal transduction. Grb2 contains an SH2 domain that interacts with phosphotyrosine-containing sequences in EGFR and other signaling molecules, and it is a promising molecular target for anti-cancer agents. To identify novel inhibitors of the Grb2 SH2 domain from natural products and their mirror-image isomers, screening systems using both enantiomers of a synthetic Grb2 SH2 domain protein were established. Two synthetic procedures for the proteins were investigated: one employed a single native chemical ligation (NCL) of two segment peptides, and the other used the N-to-C-directed NCL of three segment peptides for easier preparation...
December 29, 2016: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/27992403/themis2-lowers-the-threshold-for-b-cell-activation-during-positive-selection
#8
Daian Cheng, Mukta Deobagkar-Lele, Ekaterina Zvezdova, Seeyoung Choi, Shoji Uehara, Delphine Baup, Sophia C Bennett, Katherine R Bull, Tanya L Crockford, Helen Ferry, Claude Warzecha, Marlène Marcellin, Anne Gonzalez de Peredo, Renaud Lesourne, Consuelo Anzilotti, Paul E Love, Richard J Cornall
The positive and negative selection of lymphocytes by antigen is central to adaptive immunity and self-tolerance, yet how this is determined by different antigens is not completely understood. We found that thymocyte-selection-associated family member 2 (Themis2) increased the positive selection of B1 cells and germinal center B cells by self and foreign antigens. Themis2 lowered the threshold for B-cell activation by low-avidity, but not high-avidity, antigens. Themis2 constitutively bound the adaptor protein Grb2, src-kinase Lyn and signal transducer phospholipase γ2 (PLC-γ2), and increased activation of PLC-γ2 and its downstream pathways following B cell receptor stimulation...
February 2017: Nature Immunology
https://www.readbyqxmd.com/read/27980455/inhibition-of-integrin-%C3%AE-3-a-binding-partner-of-kallistatin-leads-to-reduced-viability-invasion-and-proliferation-in-nci-h446-cells
#9
Guoquan Wang, Xiao Wang, Xiaoping Huang, Huiyong Yang, Suqiu Pang, Xiaolan Xie, Shulan Zeng, Junsheng Lin, Yong Diao
BACKGROUND: Kallistatin is a serine proteinase inhibitor and heparin-binding protein. It is considered an endogenous angiogenic inhibitor. In addition, multiple studies demonstrated that kallistatin directly inhibits cancer cell growth. However, the molecular mechanisms underlying these effects remain unclear. METHODS: Pull-down, immunoprecipitation, and immunoblotting were used for binding experiments. To elucidate the mechanisms, integrin β3 knockdown (siRNA) or blockage (antibody treatment) on the cell surface of small the cell lung cancer NCI-H446 cell line was used...
2016: Cancer Cell International
https://www.readbyqxmd.com/read/27965114/myogenic-differentiation-depends-on-the-interplay-of-grb2-and-n-wasp
#10
Payal Mitra, Thirumaran Thanabalu
Myogenesis requires a well-coordinated withdrawal from cell cycle, morphological changes and cell fusion mediated by actin cytoskeleton. Grb2 is an adaptor protein whose central SH2 domain binds to phosphorylated tyrosine residues of activated receptors and activates intracellular signaling pathway, while its N-terminal and C-terminal SH3 domains bind to proline rich proteins such as N-WASP (Neural-Wiskott Aldrich Syndrome Protein). We found that the expression of Grb2 was increased at the beginning of differentiation and remained constant during differentiation in C2C12 myoblasts...
December 10, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27933291/endocytosis-and-physiology-insights-from-disabled-2-deficient-mice
#11
REVIEW
Wensi Tao, Robert Moore, Elizabeth R Smith, Xiang-Xi Xu
Disabled-2 (Dab2) is a clathrin and cargo binding endocytic adaptor protein, and cell biology studies revealed that Dab2 plays a role in cellular trafficking of a number of transmembrane receptors and signaling proteins. A PTB/PID domain located in the N-terminus of Dab2 binds the NPXY motif(s) present at the cytoplasmic tails of certain transmembrane proteins/receptors. The membrane receptors reported to bind directly to Dab2 include LDL receptor and its family members LRP1 and LRP2 (megalin), growth factor receptors EGFR and FGFR, and the cell adhesion receptor beta1 integrin...
2016: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/27927989/crystal-structures-and-thermodynamic-analysis-reveal-distinct-mechanisms-of-cd28-phosphopeptide-binding-to-the-sh2-domains-of-three-adaptor-proteins
#12
Satomi Inaba, Nobutaka Numoto, Shuhei Ogawa, Hisayuki Morii, Teikichi Ikura, Ryo Abe, Nobutoshi Ito, Masayuki Oda
Full activation of T cells and differentiation into effector T cells is essential for many immune responses and requires co-stimulatory signaling via the CD28 receptor. Extracellular ligand binding to CD28 recruits protein tyrosine kinases to its cytoplasmic tail, which contains a YMNM motif. Following phosphorylation of the tyrosine, the proteins growth factor receptor-bound protein 2 (Grb2), Grb2-related adaptor downstream of Shc (Gads), and p85 subunit of phosphoinositide 3-kinase may bind to pYMNM via their SH2 domains, leading to downstream signaling to distinct immune pathways...
December 6, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27926512/depression-of-oncogenecity-by-dephosphorylating-and-degrading-bcr-abl
#13
Miao Gao, Zheng-Lan Huang, Kun Tao, Qing Xiao, Xin Wang, Wei-Xi Cao, Min Xu, Jing Hu, Wen-Li Feng
Aberrant phosphorylation and overexpression of BCR-ABL fusion protein are responsible for the main pathogenesis in chronic myeloid leukemia (CML). Phosphorylated BCR-ABL Y177 recruits GRB2 adaptor and triggers leukemic RAS-MAPK and PI3K-AKT signals. In this study, we engineered a SPOA system to dephosphorylate and degrade BCR-ABL by targeting BCR-ABL Y177. We tested its effect on BCR-ABL phosphorylation and expression, as well as cell proliferation and apoptosis in CML cells. We found that SPOA remarkably dephosphorylated BCR-ABL Y177, prevented GRB2 recruitment, and uncoupled RAS-MAPK and PI3K-AKT signals...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27924253/switching-of-the-positive-feedback-for-ras-activation-by-a-concerted-function-of-sos-membrane-association-domains
#14
Yuki Nakamura, Kayo Hibino, Toshio Yanagida, Yasushi Sako
Son of sevenless (SOS) is a guanine nucleotide exchange factor that regulates cell behavior by activating the small GTPase RAS. Recent in vitro studies have suggested that an interaction between SOS and the GTP-bound active form of RAS generates a positive feedback loop that propagates RAS activation. However, it remains unclear how the multiple domains of SOS contribute to the regulation of the feedback loop in living cells. Here, we observed single molecules of SOS in living cells to analyze the kinetics and dynamics of SOS behavior...
2016: Biophysics and Physicobiology
https://www.readbyqxmd.com/read/27889231/nimbolide-inhibits-androgen-independent-prostate-cancer-cells-survival-and-proliferation-by-modulating-multiple-pro-survival-signaling-pathways
#15
P Raja Singh, E Sugantha Priya, S Balakrishnan, R Arunkumar, G Sharmila, M Rajalakshmi, J Arunakaran
BACKGROUND: Prostate cancer is the most prominent cancer in men, experiencing a relapse in disease often express high serum TNF-α levels. It has been correlated with increased cell survival and proliferation of prostate cancer cells. Previous studies reported that nimbolide, a terpenoid derived from the leaves and flowers of neem tree inhibits cancer growth through selective modulation of cell signaling pathways linked to inflammation, survival, proliferation, angiogenesis and metastasis...
December 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27887869/a-highly-diverse-and-functional-na%C3%A3-ve-ubiquitin-variant-library-for-generation-of-intracellular-affinity-reagents
#16
Isabel Leung, Nick Jarvik, Sachdev S Sidhu
We report the design, construction, and validation of a highly diverse phage-displayed naïve ubiquitin variant (Ubv) library. We first conducted a mutation tolerance scan of 27 residues and confirmed that 24 of these could be substituted by chemically diverse amino acids without compromising the display of Ubvs on phage. Subsequently, we constructed a library containing 6.8×10(10) unique members, in which these 24 positions were diversified with a degenerate codon that encodes for 6 aa that are prevalent in protein interaction sites...
January 6, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27861634/molecular-characterization-of-striated-muscle-specific-gab1-isoform-as-a-critical-signal-transducer-for-neuregulin-1-erbb-signaling-in-cardiomyocytes
#17
Taku Yasui, Takeshi Masaki, Yoh Arita, Tomohiko Ishibashi, Tadakatsu Inagaki, Makoto Okazawa, Toru Oka, Wataru Shioyama, Keiko Yamauchi-Takihara, Issei Komuro, Yasushi Sakata, Yoshikazu Nakaoka
Grb2-associated binder (Gab) docking proteins regulate signals downstream of a variety of growth factors and receptor tyrosine kinases. Neuregulin-1 (NRG-1), a member of epidermal growth factor family, plays a critical role for cardiomyocyte proliferation and prevention of heart failure via ErbB receptors. We previously reported that Gab1 and Gab2 in the myocardium are essential for maintenance of myocardial function in the postnatal heart via transmission of NRG-1/ErbB-signaling through analysis of Gab1/Gab2 cardiomyocyte-specific double knockout mice...
2016: PloS One
https://www.readbyqxmd.com/read/27845161/downregulation-of-autophagy-gene-expression-in-endometria-from-women-with-polycystic-ovary-syndrome
#18
Mirjana Sumarac-Dumanovic, Milica Apostolovic, Kristina Janjetovic, Danka Jeremic, Dusan Popadic, Aleksandar Ljubic, Jelena Micic, Jelena Dukanac-Stamenkovic, Aleksandra Tubic, Darko Stevanovic, Dragan Micic, Vladimir Trajkovic
Autophagy, a process of controlled cellular self-digestion, could be involved in cyclic remodeling of the human endometrium. We investigated endometrial mRNA expression of 23 autophagy-related (ATG) genes and transcription factors in healthy controls (n = 12) and anovulatory polycystic ovary syndrome (PCOS) patients (n = 24), as well as in their subgroup (n = 12) before and after metformin treatment. The mRNA levels of transcription factor forkhead box protein O1 (FOXO1) and several molecules involved in autophagosome formation (ATG13, RB1-inducible coiled-coil 1), autophagosome nucleation (ATG14, beclin 1, SH3-domain GRB2-like endophilin B1), autophagosome elongation (ATG3, ATG5, γ-aminobutyric acid receptor-associated protein - GABARAP), and delivery of ubiquitinated proteins to autophagosomes (sequestosome 1), were significantly reduced in anovulatory PCOS compared to healthy endometrium...
January 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27813071/what-goes-up-must-come-down-a-tripartite-dok-3-grb2-ship1-inhibitory-module-limits-bcr-signaling
#19
Michael Reth, Michael R Gold
Properly regulated immunity requires precise integration of activating and inhibitory signals. As for other lymphocytes, B cells express an antigen-specific activating receptor, the B-cell antigen receptor (BCR), and inhibitory receptors (e.g. FcγRIIb) that exercise checkpoint control on B-cell activation. Moreover, following BCR engagement, CD19 recruits proteins that amplify BCR signaling, while CD22 initiates a negative feedback loop by recruiting proteins that inhibit BCR signaling. Initial BCR signaling is mediated by protein tyrosine kinases and lipid kinases; inhibitory receptors directly antagonize the actions of these enzymes by recruiting protein tyrosine phosphatases and lipid phosphatases and positioning them close to actively signaling BCRs...
November 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27802291/actb-cdkn1b-gapdh-grb2-rhoa-and-sdcbp-were-identified-as-reference-genes-in-neuroendocrine-lung-cancer-via-the-ncounter-technology
#20
Robert Fred Henry Walter, Robert Werner, Claudia Vollbrecht, Thomas Hager, Elena Flom, Daniel Christian Christoph, Jan Schmeller, Kurt Werner Schmid, Jeremias Wohlschlaeger, Fabian Dominik Mairinger
BACKGROUND: Neuroendocrine lung cancer (NELC) represents 25% of all lung cancer cases and large patient collectives exist as formalin-fixed, paraffin-embedded (FFPE) tissue only. FFPE is controversially discussed as source for molecular biological analyses and reference genes for NELC are poorly establishes. MATERIAL AND METHODS: Forty-three representative FFPE-specimens were used for mRNA expression analysis using the digital nCounter technology (NanoString). Based on recent literature, a total of 91 mRNA targets were investigated as potential tumor markers or reference genes...
2016: PloS One
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