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https://www.readbyqxmd.com/read/29197863/proteomic-analysis-reveals-grb2-as-a-key-regulator-of-periodic-mechanical-stress-transduction-in-chondrocytes
#1
Shun Xu, Zeng Li, Zhen Wang, Chenjun Zhai, Wenwei Liang, Chunhui Zhu, Weimin Fan
BACKGROUND/AIMS: Periodic mechanical stress could significantly promote chondrocyte proliferation and matrix synthesis. However, the mechanisms underlying the ability of chondrocyte detecting and responding to periodic mechanical stimuli have not been well delineated. METHODS: Quantitative proteomic analysis was performed to construct the differently expressed proteome profiles of chondrocyte under pressure. Then a combination of Western blot, quantitative real-time PCR, lentiviral vector and histological methods were used to confirm the proteomic results and investigate the mechanoseing mechanism...
December 4, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29197740/gene-set-enrichment-analysis-and-expression-pattern-exploration-implicate-an-involvement-of-neurodevelopmental-processes-in-bipolar-disorder
#2
Thomas W Mühleisen, Céline S Reinbold, Andreas J Forstner, Lilia I Abramova, Martin Alda, Gulja Babadjanova, Michael Bauer, Paul Brennan, Alexander Chuchalin, Cristiana Cruceanu, Piotr M Czerski, Franziska Degenhardt, Sascha B Fischer, Janice M Fullerton, Scott D Gordon, Maria Grigoroiu-Serbanescu, Paul Grof, Joanna Hauser, Martin Hautzinger, Stefan Herms, Per Hoffmann, Jutta Kammerer-Ciernioch, Elza Khusnutdinova, Manolis Kogevinas, Valery Krasnov, André Lacour, Catherine Laprise, Markus Leber, Jolanta Lissowska, Susanne Lucae, Anna Maaser, Wolfgang Maier, Nicholas G Martin, Manuel Mattheisen, Fermin Mayoral, James D McKay, Sarah E Medland, Philip B Mitchell, Susanne Moebus, Grant W Montgomery, Bertram Müller-Myhsok, Lilijana Oruc, Galina Pantelejeva, Andrea Pfennig, Lejla Pojskic, Alexey Polonikov, Andreas Reif, Fabio Rivas, Guy A Rouleau, Lorena M Schenk, Peter R Schofield, Markus Schwarz, Fabian Streit, Jana Strohmaier, Neonila Szeszenia-Dabrowska, Alexander S Tiganov, Jens Treutlein, Gustavo Turecki, Helmut Vedder, Stephanie H Witt, Thomas G Schulze, Marcella Rietschel, Markus M Nöthen, Sven Cichon
BACKGROUND: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. METHODS: We conducted gene set enrichment analyses (GSEA) using 2...
November 14, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/29182244/allosteric-modulation-of-grb2-recruitment-to-the-intrinsically-disordered-scaffold-protein-lat-by-remote-site-phosphorylation
#3
William Y C Huang, Jonathon A Ditlev, Han-Kuei Chiang, Michael K Rosen, Jay T Groves
Tyrosine phosphorylation of membrane receptors and scaffold proteins followed by recruitment of SH2 domain-containing adaptor proteins constitutes a central mechanism of intracellular signal transduction. During early T-cell receptor (TCR) activation, phosphorylation of linker for activation of T cells (LAT) leading to recruitment of adaptor proteins, including Grb2, is one prototypical example. LAT contains multiple modifiable sites, and this multivalency may provide additional layers of regulation, although this is not well understood...
November 28, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29173143/the-role-of-grb2-in-cancer-and-peptides-as-grb2-antagonists
#4
Muhammad Ijaz, Muhammad Shahbaz, Wenjie Jiang, Abdel Hamid Fathy, Effat Un Nesa, Wang Feng Shan
Growth factor receptor-bound protein 2 (Grb2) is a 25 kDa adaptor protein, which was originally discovered to accomplish basic cellular events such as cell growth, cell proliferation, and metabolism. However, recent studies evidenced that Grb2 was largely involved in multiple tumor malignancies. The mature Grb2 is a 217 amino acid sequence, which consists of one Src homology 2 (SH2) domain flanked by two Src homology 3 (SH3) domains. Using these binding motives, the ubiquitously expressed Grb2 acts as an intermediate between cell-surface activated receptors and downstream targets...
November 23, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/29162725/src-homology-2-domains-enhance-tyrosine-phosphorylation-in-vivo-by-protecting-binding-sites-in-their-target-proteins-from-dephosphorylation
#5
Joshua A Jadwin, Timothy G Curran, Adam T Lafontaine, Forest M White, Bruce J Mayer
Phosphotyrosine (pY)-dependent signaling is critical for many cellular processes. It is highly dynamic, as signal output depends not only on phosphorylation and dephosphorylation rates, but also on the rates of binding and dissociation of effectors containing phosphotyrosine-dependent binding modules such as Src Homology 2 (SH2) and phosphotyrosine-binding (PTB) domains. Previous in vitro studies suggested that binding of SH2 and PTB domains can enhance protein phosphorylation by protecting the sites bound by these domains from phosphatase-mediated dephosphorylation...
November 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29137268/understanding-the-mechanism-of-binding-between-gab2-and-the-c-terminal-sh3-domain-from-grb2
#6
Angelo Toto, Daniela Bonetti, Alfonso De Simone, Stefano Gianni
Gab2 is a large disordered protein that regulates several cellular signalling pathways and is overexpressed in different forms of cancer. Because of its disordered nature, a detailed characterization of the mechanisms of recognition between Gab2 and its physiological partners is particularly difficult. Here we provide a detailed kinetic characterization of the binding reaction between Gab2 and the C-terminal SH3 domain of the growth factor receptor-bound protein 2 (Grb2). We demonstrate that Gab2 folds upon binding following an induced fit type mechanism, whereby recognition is characterized by the formation of an intermediate, in which Gab2 is primarily disordered...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29133857/pdgfr-modulated-mir-23b-cluster-and-mir-125a-5p-suppress-lung-tumorigenesis-by-targeting-multiple-components-of-kras-and-nf-kb-pathways
#7
Srivatsava Naidu, Lei Shi, Peter Magee, Justin D Middleton, Alessandro Laganá, Sudhakar Sahoo, Hui Sun Leong, Melanie Galvin, Kristopher Frese, Caroline Dive, Vincenza Guzzardo, Matteo Fassan, Michela Garofalo
In NSCLC alterations in PDGF receptors are markers of worst prognosis and efficient targeting of these receptors is yet to be achieved. In this study, we explored PDGFR-regulated microRNAs demonstrating that miR-23b cluster and miR-125a-5p are downregulated by increased expression of PDGFR-α or PDGFR-β in NSCLC cells. Mechanistically, the expression of these microRNAs is positively regulated by p53 and negatively modulated by NF-kB p65. Forced expression of miR-23b cluster or miR-125a-5p enhanced drug sensitivity and suppressed invasiveness of NSCLC cells by silencing several genes involved in oncogenic KRAS and NF-kB pathways, including SOS1, GRB2, IQGAP1, RALA, RAF-1, IKKβ, AKT2, ERK2 and KRAS itself...
November 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29074618/epidermal-growth-factor-receptors-containing-a-single-tyrosine-in-their-c-terminal-tail-bind-different-effector-molecules-and-are-signaling-competent
#8
Kamaldeep Gill, Jennifer L Macdonald-Obermann, Linda J Pike
The EGF receptor is a classic receptor tyrosine kinase. It contains nine tyrosines in its C-terminal tail, many of which are phosphorylated and bind proteins containing SH2 or phosphotyrosine-binding (PTB) domains. To determine how many and which tyrosines are required to enable EGF receptormediated signaling, we generated a series of EGF receptors that contained only one tyrosine in their C-terminal tail. Assays of the signaling capabilities of these single-Tyr EGF receptors, indicated that they can activate a range of downstream signaling pathways, including MAP kinase and Akt...
October 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29047011/comparing-pharmacophore-models-derived-from-crystallography-and-nmr-ensembles
#9
Phani Ghanakota, Heather A Carlson
NMR and X-ray crystallography are the two most widely used methods for determining protein structures. Our previous study examining NMR versus X-Ray sources of protein conformations showed improved performance with NMR structures when used in our Multiple Protein Structures (MPS) method for receptor-based pharmacophores (Damm, Carlson, J Am Chem Soc 129:8225-8235, 2007). However, that work was based on a single test case, HIV-1 protease, because of the rich data available for that system. New data for more systems are available now, which calls for further examination of the effect of different sources of protein conformations...
November 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29045874/dynamic-scaling-analysis-of-molecular-motion-within-the-lat-grb2-sos-protein-network-on%C3%A2-membranes
#10
William Y C Huang, Han-Kuei Chiang, Jay T Groves
Biochemical signaling pathways often involve proteins with multiple, modular interaction domains. Signaling activates binding sites, such as by tyrosine phosphorylation, which enables protein recruitment and growth of networked protein assemblies. Although widely observed, the physical properties of the assemblies, as well as the mechanisms by which they function, remain largely unknown. Here we examine molecular mobility within LAT:Grb2:SOS assemblies on supported membranes by single-molecule tracking. Trajectory analysis reveals a discrete temporal transition to subdiffusive motion below a characteristic timescale, indicating that the LAT:Grb2:SOS assembly has the dynamical structure of a loosely entangled polymer...
October 17, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29018805/insight-into-the-selectivity-of-the-g7-18nate-inhibitor-peptide-for-the-grb7-sh2-domain-target
#11
Gabrielle M Watson, William A H Lucas, Menachem J Gunzburg, Jacqueline A Wilce
Growth factor receptor bound protein 7 (Grb7) is an adaptor protein with established roles in the progression of both breast and pancreatic cancers. Through its C-terminal SH2 domain, Grb7 binds to phosphorylated tyrosine kinases to promote proliferative and migratory signaling. Here, we investigated the molecular basis for the specificity of a Grb7 SH2-domain targeted peptide inhibitor. We identified that arginine 462 in the BC loop is unique to Grb7 compared to Grb2, another SH2 domain bearing protein that shares the same consensus binding motif as Grb7...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28993193/%C3%AE-lipoic-acid-inhibits-human-lung-cancer-cell-proliferation-through-grb2-mediated-egfr-downregulation
#12
Lan Yang, Ya Wen, Guoqing Lv, Yuntao Lin, Junlong Tang, Jingxiao Lu, Manqiao Zhang, Wen Liu, Xiaojuan Sun
BACKGROUND: Alpha lipoic acid (α -LA) is a naturally occurring antioxidant and metabolic enzyme co-factor. Recently, α -LA has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α -LA on non-small cell lung cancer (NSCLC) development remain unclear. METHODS: The CCK-8 assay was used to assess cell proliferation in NSCLC cell lines after α -LA treatment. The expression of growth factor receptor-bound protein 2 (Grb2), cyclin-dependent kinase (CDK)-2, CDK4, CDK6, Cyclin D3, Cyclin E1, Ras, c-Raf, epidermal growth factor receptor (EGFR), ERK1/2 and activated EGFR and ERK1/2 was evaluated by western blotting...
December 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28978467/m-%C3%A2-tuberculosis-initiated-human-mannose-receptor-signaling-regulates-macrophage-recognition-and-vesicle-trafficking-by-fcr%C3%AE-chain-grb2-and-shp-1
#13
Murugesan V S Rajaram, Eusondia Arnett, Abul K Azad, Evelyn Guirado, Bin Ni, Abigail D Gerberick, Li-Zhen He, Tibor Keler, Lawrence J Thomas, William P Lafuse, Larry S Schlesinger
Despite its prominent role as a C-type lectin (CTL) pattern recognition receptor, mannose receptor (MR, CD206)-specific signaling molecules and pathways are unknown. The MR is highly expressed on human macrophages, regulating endocytosis, phagocytosis, and immune responses and mediating Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages, thereby limiting phagosome-lysosome (P-L) fusion. We identified human MR-associated proteins using phosphorylated and non-phosphorylated MR cytoplasmic tail peptides...
October 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28973902/drk-mediated-signaling-to-rho-kinase-is-required-for-anesthesia-resistant-memory-in-drosophila
#14
Vasileia Kotoula, Anastasios Moressis, Ourania Semelidou, Efthimios M C Skoulakis
Anesthesia-resistant memory (ARM) was described decades ago, but the mechanisms that underlie this protein synthesis-independent form of consolidated memory in Drosophila remain poorly understood. Whether the several signaling molecules, receptors, and synaptic proteins currently implicated in ARM operate in one or more pathways and how they function in the process remain unclear. We present evidence that Drk, the Drosophila ortholog of the adaptor protein Grb2, is essential for ARM within adult mushroom body neurons...
October 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28964849/grb2-regulates-the-proliferation-of-hematopoietic-stem-and-progenitors-cells
#15
Catherine Frelin, Yishai Ofran, Julie Ruston, Michal Hayun, Yael Derdikman, Yasmine Khier, Kinneret Rozales, Benjamin Brenner, Norman Iscove, Tony Pawson, Igal Louria-Hayon
Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines, little is known about the intracellular signaling pathways that are activated by cytokines upon binding to their receptors. Our study showed that Growth factor receptor-bound protein 2 (Grb2) mRNAs are preferentially expressed in HSC compared to progenitors and differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a rapid decline of erythroid and myeloid progenitors and a progressive decline of HSC numbers in steady state conditions...
December 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28951535/dimerization-of-the-adaptor-gads-facilitates-antigen-receptor-signaling-by-promoting-the-cooperative-binding-of-gads-to-the-adaptor-lat
#16
Sigalit Sukenik, Maria P Frushicheva, Cecilia Waknin-Lellouche, Enas Hallumi, Talia Ifrach, Rose Shalah, Dvora Beach, Reuven Avidan, Ilana Oz, Evgeny Libman, Ami Aronheim, Oded Lewinson, Deborah Yablonski
The accurate assembly of signalosomes centered on the adaptor protein LAT (linker of activated T cells) is required for antigen receptor signaling in T cells and mast cells. During signalosome assembly, members of the growth factor receptor-bound protein 2 (Grb2) family of cytosolic adaptor proteins bind cooperatively to LAT through interactions with its phosphorylated tyrosine (pTyr) residues. We demonstrated the Src homology 2 (SH2) domain-mediated dimerization of the Grb2 family member, Grb2-related adaptor downstream of Shc (Gads)...
September 26, 2017: Science Signaling
https://www.readbyqxmd.com/read/28938536/integrating-omics-data-and-protein-interaction-networks-to-prioritize-driver-genes-in-cancer
#17
Tiejun Zhang, Di Zhang
Although numerous approaches have been proposed to discern driver from passenger, identification of driver genes remains a critical challenge in the cancer genomics field. Driver genes with low mutated frequency tend to be filtered in cancer research. In addition, the accumulation of different omics data necessitates the development of algorithmic frameworks for nominating putative driver genes. In this study, we presented a novel framework to identify driver genes through integrating multi-omics data such as somatic mutation, gene expression, and copy number alterations...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28936468/gfp-grb2-translocation-assay-using-high-content-imaging-to-screen-for-modulators-of-egfr-signaling
#18
Julia Petschnigg, Robin Ketteler
High-content screening is a useful tool to understand complex cellular processes and to identify genes, proteins or small molecule compounds that modulate such pathways. High-content assays monitor the function of a protein or pathway by visualizing a change in an image-based readout, such as a change in the localization of a reporter protein. Examples of this can be the translocation of a fluorescently tagged protein from the cytoplasm to the nucleus or to the plasma membrane. One protein that is known to undergo such translocation is the Growth Factor Receptor-bound protein 2 (GRB2) that is recruited to the plasma membrane upon stimulation of a growth factor receptor and subsequently undergoes internalization...
September 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/28930697/overexpression-of-muc1-and-genomic-alterations-in-its-network-associate-with-prostate-cancer-progression
#19
Xiaozeng Lin, Yan Gu, Anil Kapoor, Fengxiang Wei, Tariq Aziz, Diane Ojo, Yanzhi Jiang, Michael Bonert, Bobby Shayegan, Huixiang Yang, Khalid Al-Nedawi, Pierre Major, Damu Tang
We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN(-/-) mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n=300), testing (n=185), and validation (n=194) cohort...
November 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28912526/mpzl1-forms-a-signalling-complex-with-grb2-adaptor-and-ptpn11-phosphatase-in-her2-positive-breast-cancer-cells
#20
Alice Beigbeder, François J M Chartier, Nicolas Bisson
HER2/ErbB2 is overexpressed in a significant fraction of breast tumours and is associated with a poor prognosis. The adaptor protein GRB2 interacts directly with activated HER2 and is sufficient to transmit oncogenic signals. However, the consequence of HER2 activation on global GRB2 signalling networks is poorly characterized. We performed GRB2 affinity purification combined with mass spectrometry analysis of associated proteins in a HER2+ breast cancer model to delineate GRB2-nucleated protein interaction networks...
September 14, 2017: Scientific Reports
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