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Ulrich Baumgartner, Fabienne Berger, Ali Hashemi Gheinani, Sabrina Sofia Burgener, Katia Monastyrskaya, Erik Vassella
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations enable constitutive active downstream signaling of PI3K/AKT, KRAS/ERK and JAK/STAT pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of non-small cell lung cancer (NSCLC). In addition, such EGFR mutations increase the susceptibility of patients with NSCLC to tyrosine kinase inhibitor (TKI) therapy, but treated patients will invariably relapse with resistant disease...
February 19, 2018: Molecular Cancer
Sara Sopeña-Torres, Lucía Jordá, Clara Sánchez-Rodríguez, Eva Miedes, Viviana Escudero, Sanjay Swami, Gemma López, Mariola Piślewska-Bednarek, Ines Lassowskat, Justin Lee, Yangnan Gu, Sabine Haigis, Danny Alexander, Sivakumar Pattathil, Antonio Muñoz-Barrios, Pawel Bednarek, Shauna Somerville, Paul Schulze-Lefert, Michael G Hahn, Dierk Scheel, Antonio Molina
Mitogen-activated protein kinases (MAPKs) cascades play essential roles in plants by transducing developmental cues and environmental signals into cellular responses. Among the latter are microbe-associated molecular patterns perceived by pattern recognition receptors (PRRs), which trigger immunity. We found that YODA (YDA) - a MAPK kinase kinase regulating several Arabidopsis developmental processes, like stomatal patterning - also modulates immune responses. Resistance to pathogens is compromised in yda alleles, whereas plants expressing the constitutively active YDA (CA-YDA) protein show broad-spectrum resistance to fungi, bacteria, and oomycetes with different colonization modes...
February 16, 2018: New Phytologist
Clement M Potel, Miao-Hsia Lin, Albert J R Heck, Simone Lemeer
Here we demonstrate that biomolecular contaminants, such as nucleic acid molecules, can seriously interfere with IMAC based phosphopeptide enrichments. We address and largely solve this issue, developing a robust protocol implementing methanol/chloroform protein precipitation and enzymatic digestion using benzonase, which degrades all forms of DNA and RNA, prior to IMAC-column loading. This simple procedure resulted in a drastic increase of enrichment sensitivity, enabling the identification of around 17,000 unique phosphopeptides and 12,500 unambiguously localized phosphosites in human cell-lines from a single LC-MS/MS run, constituting a 50% increase when compared to the standard protocol...
February 15, 2018: Molecular & Cellular Proteomics: MCP
Kevin Shee, Wei Yang, John W Hinds, Riley A Hampsch, Frederick S Varn, Nicole A Traphagen, Kishan Patel, Chao Cheng, Nicole P Jenkins, Arminja N Kettenbach, Eugene Demidenko, Philip Owens, Anthony C Faber, Todd R Golub, Ravid Straussman, Todd W Miller
Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance...
February 7, 2018: Journal of Experimental Medicine
Mingjin Zou, Jing Wang, Jidong Gao, Hui Han, Yi Fang
The incidence of breast cancer has been increasing in China and the age of breast cancer onset is earlier compared with Western countries. Compounds commonly used in Traditional Chinese Medicine (TCM) are an important source of anticancer drugs. Ginseng is one of the most common medicines used in TCM. Ginsenosides, which are saponins found in the ginseng plant, are the major active components responsible for the chemopreventive effects of ginseng in cancer. However, the mechanisms by which ginsenosides exert their anticancer effects remain elusive...
March 2018: Oncology Letters
Daniel Bucio-Noble, Liisa Kautto, Christoph Krisp, Malcolm S Ball, Mark P Molloy
Sugarcane is an important crop grown in tropical regions for sugar, and for ethanol production. Sugarcane is also a source of phytochemicals but its nutraceutical potential has been under-explored. We show that ethanol extracts of whole dried sugarcane (WDS) recovers a rich content of polyphenols, flavonoids and antioxidant activity that act on inflammatory mediator proteins. To investigate the mechanisms of this activity, we stimulated SW480 colon cancer cells with lipopolysaccharide, exposed cells to WDS and quantitated changes to the proteome and phosphoproteome using label-free mass spectrometry...
February 10, 2018: Journal of Proteomics
Zhihuan Li, Zon Weng Lai, Romain Christiano, Felipe Gazos-Lopes, Tobias C Walther, Robert V Farese
Obesity is tightly linked to hepatic steatosis and insulin resistance. One feature of this association is the paradox of selective insulin resistance: insulin fails to suppress hepatic gluconeogenesis but activates lipid synthesis in the liver. How lipid accumulation interferes selectively with some branches of hepatic insulin signaling is not well understood. Here we provide a resource, based on unbiased approaches and established in a simple cell culture system, to enable investigations of the phenomenon of selective insulin resistance...
February 5, 2018: Molecular & Cellular Proteomics: MCP
Xingkang Wu, Zhenyu Li, Yuemao Shen
BACKGROUND: Mitosis, the most dramatic event in the cell cycle, involves the reorganization of virtually all cellular components. Antimitotic agents are useful for dissecting the mechanism of this reorganization. Previously, we found that the small molecule CS1 accumulates cells in G2/M phase [1], but the mechanism of its action remains unknown. METHODS: Cell cycle analysis, live cell imaging and nuclear staining were used. Chromosomal morphology was detected by chromosome spreading...
January 30, 2018: Biochimica et Biophysica Acta
Cynthia de la Fuente, Chelsea Pinkham, Deemah Dabbagh, Brett Beitzel, Aura Garrison, Gustavo Palacios, Kimberley Alex Hodge, Emanuel F Petricoin, Connie Schmaljohn, Catherine E Campbell, Aarthi Narayanan, Kylene Kehn-Hall
Rift Valley fever virus (RVFV) infects both ruminants and humans leading to a wide variance of pathologies dependent on host background and age. Utilizing a targeted reverse phase protein array (RPPA) to define changes in signaling cascades after in vitro infection of human cells with virulent and attenuated RVFV strains, we observed high phosphorylation of Smad transcription factors. This evolutionarily conserved family is phosphorylated by and transduces the activation of TGF-β superfamily receptors. Moreover, we observed that phosphorylation of Smad proteins required active RVFV replication and loss of NSs impaired this activation, further corroborating the RPPA results...
2018: PloS One
Zheng Li, Meng Li, Xin Li, Jianzeng Xin, Ying Wang, Qingwu W Shen, Dequan Zhang
A quantitative analysis of protein phosphorylation in ovine LTL muscle with different color stability was performed in the present study using TMT labeling in combination with TiO2 phosphopeptide enrichment. A total of 3412 phosphopeptides assigned to 1070 phosphoproteins were identified by mass spectrometry, of which 243 proteins were detected to be differentially phosphorylated between muscles of different color stability. Among these differentially phosphorylated proteins, 27 phosphoproteins were identified to be key color-related proteins by informatics analysis...
May 30, 2018: Food Chemistry
Isidro Ferrer, Meritxell Aguiló García, Irene López González, Daniela Diaz Lucena, Aina Roig Villalonga, Margarita Carmona Tech, Franc Llorens, Paula Garcia-Esparcia, Alejandra Martinez-Maldonado, Margalida Frau Mendez, Benjamín Torrejón Escribano, Joan Josep Bech Serra, Eduard Sabido, Carolina de la Torre Gómez, José Antonio Del Rio
Aging-related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau-bearing astrocytes: thorn-shaped astrocytes (TSAs) and granular/fuzzy astrocytes in the brain of old-aged individuals. The present study is focused on TSAs in rare forms of ARTAG with no neuronal tau pathology or restricted to entorhinal and transentorhinal cortices, to avoid bias from associated tauopathies. TSAs show 4Rtau phosphorylation at several specific sites and abnormal tau conformation, but they lack ubiquitin and they are not immunostained with tau-C3 antibodies which recognize truncated tau at Asp421...
February 3, 2018: Brain Pathology
Özge Karayel, Erdem Şanal, Sven H Giese, Zeynep Cansu Üretmen Kagıalı, Ayşe Nur Polat, Chi-Kuo Hu, Bernhard Y Renard, Nurcan Tuncbag, Nurhan Özlü
The successful completion of cytokinesis requires the coordinated activities of diverse cellular components including membranes, cytoskeletal elements and chromosomes that together form partly redundant pathways, depending on the cell type. The biochemical analysis of this process is challenging due to its dynamic and rapid nature. Here, we systematically compared monopolar and bipolar cytokinesis and demonstrated that monopolar cytokinesis is a good surrogate for cytokinesis and it is a well-suited system for global biochemical analysis in mammalian cells...
February 2, 2018: Scientific Reports
Carolina Angelica Parada, Joshua Osbun, Sumanpreet Kaur, Youssef Yakkioui, Min Shi, Catherine Pan, Tina Busald, Yigit Karasozen, Luis Francisco Gonzalez-Cuyar, Robert Rostomily, Jing Zhang, Manuel Ferreira
There is a need to better understand meningioma oncogenesis for biomarker discovery and development of targeted therapies. Histological or genetic criteria do not accurately predict aggressiveness. Post-translational studies in meningioma progression are lacking. In the present work, we introduce a combination of mass spectrometry-based phosphoproteomics and peptide array kinomics to profile atypical and anaplastic (high-grade) meningiomas. In the discovery set of fresh-frozen tissue specimens (14), the A-kinase anchor protein 12 (AKAP12) protein was found downregulated across the grades...
February 1, 2018: Scientific Reports
Klaus Faserl, Bettina Sarg, Peter Gruber, Herbert H Lindner
Capillary electrophoresis coupled to mass spectrometry is a very efficient analytical method for the analysis of post-translational modifications because of its high separation efficiency and high detection sensitivity. Here we applied CE-MS using three differently coated separation capillaries for in-depth analysis of a set of 70 synthetic post-translationally modified peptides (including phosphorylation, acetylation, methylation, and nitration). We evaluated the results in terms of peptide detection and separation characteristics and found that the use of a neutrally coated capillary resulted in highest overall signal intensity of singly modified peptides...
February 1, 2018: Electrophoresis
Augusto S Nascimento, Luisa L Peres, Alessandra V S Fari, Renato Milani, Rodrigo A Silva, Celio Jr da Costa Fernandes, Maikel P Peppelenbosch, Carmen V Ferreira-Halder, Willian F Zambuzzi
Breast cancer is responsible for 25% of cancer cases and 15% of cancer death among women. Treatment is usually prolonged and hampered by the development of chemoresistance. The molecular mechanisms maintaining the chemoresistant phenotype remains, however, largely obscure. As kinase signaling in general is highly drugable, identification of kinases essential for maintaining chemoresistance could prove therapeutically useful. Hence we compared cellular kinase activity in chemotherapy resistant MCF7Res cells to chemotherapy-sensitive MCF cells using a peptide array approach that provides an atlas of cellular kinase activities and consequently, predominant pathways can be identified...
December 29, 2017: Oncotarget
Kyota Fujita, Xigui Chen, Hidenori Homma, Kazuhiko Tagawa, Mutsuki Amano, Ayumu Saito, Seiya Imoto, Hiroyasu Akatsu, Yoshio Hashizume, Kozo Kaibuchi, Satoru Miyano, Hitoshi Okazawa
Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCα as the kinase responsible for the early-stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss...
January 30, 2018: Nature Communications
Lee Roth, Swati Srivastava, Moshit Lindzen, Aldema Sas-Chen, Michal Sheffer, Mattia Lauriola, Yehoshua Enuka, Ashish Noronha, Maicol Mancini, Sara Lavi, Gabi Tarcic, Gur Pines, Nava Nevo, Ori Heyman, Tamar Ziv, Oscar M Rueda, Davide Gnocchi, Eli Pikarski, Arie Admon, Carlos Caldas, Yosef Yarden
Mutations mimicking growth factor-induced proliferation and motility characterize aggressive subtypes of mammary tumors. To unravel currently unknown players in these processes, we performed phosphoproteomic analysis on untransformed mammary epithelial cells (MCF10A) that were stimulated in culture with epidermal growth factor (EGF). We identified ladinin-1 (LAD1), a largely uncharacterized protein to date, as a phosphorylation-regulated mediator of the EGF-to-ERK pathway. Further experiments revealed that LAD1 mediated the proliferation and migration of mammary cells...
January 30, 2018: Science Signaling
Yesenia Herrera, Sandra Contreras, Magdalena Hernández, Laura Álvarez, Yolanda Mora, Sergio Encarnación-Guevara
BACKGROUND: A key process in cell regulation is protein phosphorylation, which is catalyzed by protein kinases and phosphatases. However, phosphoproteomics studies are difficult because of the complexity of protein phosphorylation and the number of phosphorylation sites. METHODS: We describe an efficient approach analyzing phosphopeptides in single, separated protein by two-dimensional gel electrophoresis. In this method, a titanium oxide (TiO2)-packed NuTip is used as a phosphopeptide trap, together with displacers as lactic acid in the loading buffer to increase the efficiency of the interaction between TiO2 and phosphorylated peptides...
May 2017: Boletín Médico del Hospital Infantil de México
Clement M Potel, Miao-Hsia Lin, Albert J R Heck, Simone Lemeer
For decades, major difficulties in analyzing histidine phosphorylation have limited the study of phosphohistidine signaling. Here we report a method revealing widespread and abundant protein histidine phosphorylation in Escherichia coli. We generated an extensive E. coli phosphoproteome data set, in which a remarkably high percentage (∼10%) of phosphorylation sites are phosphohistidine sites. This resource should help enable a better understanding of the biological function of histidine phosphorylation.
January 29, 2018: Nature Methods
Aradhana Awasthi, Delphine C M Rolland, Janet Ayello, Carmella van de Ven, Venkatesha Basrur, Kevin Conlon, Damian Fermin, Matthew J Barth, Christian Klein, Kojo S J Elenitoba-Johnson, Megan S Lim, Mitchell S Cairo
We recently demonstrated that obinutuzumab (GA101), a novel glycoengineered type II CD20 Ab compared to rituximab (RTX) mediates significantly enhanced antibody-dependent cell cytotoxicity (ADCC) in vitro and increased overall survival in a Burkitt lymphoma (BL) xenograft non-obese diabetic severe combined immunodeficiency gamma (NSG) model. In this study we compared the phosphoproteomic changes by pathway analysis following obinutuzumab vs RTX against RTX-sensitive (Raji) and -resistant BL (Raji4RH). Phosphoproteomic analyses were performed by mass-spectrometry (MS)-based label-free quantitative phosphoproteomic profiling...
December 26, 2017: Oncotarget
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