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Jacqueline R Ha, Ryuhjin Ahn, Harvey W Smith, Valerie Sabourin, Steven Hėbert, Eduardo Cepeda Cañedo, Young Kyuen Im, Claudia Kleinman, William J Muller, Josie Ursini-Siegel
The commonality between most phospho-tyrosine signaling networks is their shared use of adaptor proteins to transduce mitogenic signals. ShcA (SHC1) is one such adaptor protein that employs two phospho-tyrosine binding domains (PTB and SH2) and key phospho-tyrosine residues to promote mammary tumorigenesis. Receptor tyrosine kinases (RTKs), such as ErbB2, engage the ShcA PTB domain to promote breast tumorigenesis by engaging Grb2 downstream of the ShcA tyrosine phosphorylation sites to activate AKT/mTOR signaling...
February 16, 2018: Molecular Cancer Research: MCR
Jennifer E Howes, Denis T Akan, Michael C Burns, Olivia W Rossanese, Alex G Waterson, Stephen W Fesik
Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacological modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS mutant isoforms...
February 13, 2018: Molecular Cancer Therapeutics
Huan Wang, Hui He, Hongmei Meng, Yang Cui, Wenbo Wang
To investigate the association between the expression of growth factor receptor binding protein 2-associated binding protein 2 (Gab2) in human osteosarcoma as well as the effects of Gab2 on invasion and metastasis, human MG-63 osteosarcoma cells were transfected with small interfering (si)RNA plasmid. Gab2 protein and mRNA expression levels were detected using western blotting and reverse transcription-polymerase chain reaction, respectively. The cell migration and invasion abilities were detected using in vitro chemotaxis and invasion assays, respectively, following siRNA vector expression...
January 2018: Oncology Letters
Danni Chen, Wengong Si, Jiaying Shen, Chengyong Du, Weiyang Lou, Chang Bao, Huilin Zheng, Jie Pan, Guansheng Zhong, Liang Xu, Peifen Fu, Weimin Fan
Drug resistance remains a major problem in the treatment of conventional chemotherapeutic agents in breast cancers. Owing to heterogeneity and complexity of chemoresistance mechanisms, most efforts that focus on a single pathway were unsuccessful, and exploring novel personalized therapeutics becomes urgent. By a system approach, we identified that microRNA-27b-3p (miR-27b), a miRNA deleted in breast cancer tissues and cell lines, has a master role in sensitizing breast cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo...
February 7, 2018: Cell Death & Disease
Tamica N Collins, Yingyu Mao, Hongge Li, Michael Bouaziz, Angela Hong, Gen-Sheng Feng, Fen Wang, Lawrence A Quilliam, Lin Chen, Taeju Park, Tom Curran, Xin Zhang
Specific cell shapes are fundamental to the organization and function of multicellular organisms. Fibroblast Growth Factor (FGF) signaling induces the elongation of lens fiber cells during vertebrate lens development. Nonetheless, exactly how this extracellular FGF signal is transmitted to the cytoskeletal network has previously not been determined. Here, we show that the Crk family of adaptor proteins, Crk and Crkl, are required for mouse lens morphogenesis but not differentiation. Genetic ablation and epistasis experiments demonstrated that Crk and Crkl play overlapping roles downstream of FGF signaling in order to regulate lens fiber cell elongation...
January 23, 2018: ELife
Ismini Lasithiotaki, Eliza Tsitoura, Anastasios Koutsopoulos, Eleni Lagoudaki, Chara Koutoulaki, George Pitsidianakis, Demetrios A Spandidos, Nikolaos M Siafakas, George Sourvinos, Katerina M Antoniou
Merkel Cell Polyoma Virus (MCPyV) infection has been associated with non-small cell lung cancer (NSCLC). Viruses can manipulate cellular miRNAs or have a profound impact on cellular miRNA expression to control host regulatory pathways. In this study, we evaluated the expression profiles of cancer-associated and virally affected host microRNAs miR-21, miR-145, miR-146a, miR-155, miR-302c, miR-367 and miR-376c in a series of NSCLC tissue samples as well as in samples from "healthy" sites, distant from the tumour region that were either positive or negative for MCPyV DNA...
December 22, 2017: Oncotarget
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
Pallavi Mohanty, Sonika Bhatnagar
Focal adhesion kinase (FAK) is required for signaling in the heart. S910 phosphorylated FAK is known to cause pathological cardiac hypertrophy. The switching of FAK between its inactive (-i), activated (-a) and hyperactive (-h) state is controlled by phosphorylation. FAK consists of three domains, namely: FERM, Kinase, and FAT joined by linkers L1 and L2. The structural basis of FAK phosphorylation and signaling to the downstream pathways is not understood. In this work, we carried out homology modeling and domain assembly of full length human iFAK and aFAK...
December 19, 2017: Journal of Molecular Graphics & Modelling
A Yu Ratushnyy, L B Buravkova
The expression of 84 focal adhesion genes of multipotent mesenchymal stromal cells (MMSCs) after 96-h microgravity simulation at 3D clinorotation was studied. The upregulation of ITGA6, ITGA7, BCAR1, GRB2, CAV1, and DIAPH1 and the downregulation of ITGA11, ITGAV, ITGB1, PTEN, PTK2 (FAK), ARHGAP5, DOCK1, ROCK2, and AKT3 was found. These changes at the transcriptional level may be a cause of the reduction of the osteogenic potential of MMSCs and their ability to migration and adhesion in microgravity.
November 2017: Doklady. Biochemistry and Biophysics
Chaojie Liang, Yingchen Xu, Hua Ge, Bingchen Xing, Guanqun Li, Guangming Li, Jixiang Wu
Recent studies have shown that miR-564 is closely related to the development of various tumors, including breast cancer, lung cancer and glioma. However, few studies have examined miR-564 in hepatocellular carcinoma (HCC). Here, we demonstrated that miR-564 expression in HCC tissues was lower than that in adjacent noncancerous tissues and that miR-564 expression was associated with tumor size, tumor number and vein invasion. Bioinformatics analyses showed that low levels of miR-564 were correlated with poor prognosis...
December 8, 2017: Oncotarget
Qing Wei, Hongliang Liu, Zhiying Ai, Yongyan Wu, Yingxiang Liu, Zhaopeng Shi, Xuexue Ren, Zekun Guo
BACKGROUND/AIMS: Self-renewal is one of the most important features of embryonic stem (ES) cells. SC1 is a small molecule modulator that effectively maintains the self-renewal of mouse ES cells in the absence of leukemia inhibitory factor (LIF), serum and feeder cells. However, the mechanism by which SC1 maintains the undifferentiated state of mouse ES cells remains unclear. METHODS: In this study, microarray and small RNA deep-sequencing experiments were performed on mouse ES cells treated with or without SC1 to identify the key genes and microRNAs that contributed to self-renewal...
December 12, 2017: Cellular Physiology and Biochemistry
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
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
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
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
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
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
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
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
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
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