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Marise R Heerma van Voss, Kai Kammers, Farhad Vesuna, Justin Brilliant, Yehudit Bergman, Saritha Tantravedi, Xinyan Wu, Robert N Cole, Andrew Holland, Paul J van Diest, Venu Raman
DDX3 is an RNA helicase with oncogenic properties. The small molecule inhibitor RK-33 is designed to fit into the ATP binding cleft of DDX3 and hereby block its activity. RK-33 has shown potent activity in preclinical cancer models. However, the mechanism behind the antineoplastic activity of RK-33 remains largely unknown. In this study we used a dual phosphoproteomic and single cell tracking approach to evaluate the effect of RK-33 on cancer cells. MDA-MB-435 cells were treated for 24 hours with RK-33 or vehicle control...
April 20, 2018: Translational Oncology
Brittany N Pease, Edward L Huttlin, Mark P Jedrychowski, Dominique Dorin-Semblat, Daniela Sebastiani, Daniel T Segarra, Bracken F Roberts, Ratna Chakrabarti, Christian Doerig, Steven P Gygi, Debopam Chakrabarti
PfPK7 is an "orphan" kinase displaying regions of homology to multiple protein kinase families. PfPK7 functions in regulating parasite proliferation/development as evident from the phenotype analysis of knockout parasites. Despite this regulatory role, the functions of PfPK7 in signaling pathways are not known. To better understand PfPK7-regulated phosphorylation events, we performed isobaric tag-based quantitative comparative phosphoproteomics of the schizont and segmenter stages from wild-type and pfpk7- parasite lines...
April 20, 2018: Journal of Proteome Research
Sarah H Ross, Doreen A Cantrell
The discovery of interleukin-2 (IL-2) changed the molecular understanding of how the immune system is controlled. IL-2 is a pleiotropic cytokine, and dissecting the signaling pathways that allow IL-2 to control the differentiation and homeostasis of both pro- and anti-inflammatory T cells is fundamental to determining the molecular details of immune regulation. The IL-2 receptor couples to JAK tyrosine kinases and activates the STAT5 transcription factors. However, IL-2 does much more than control transcriptional programs; it is a key regulator of T cell metabolic programs...
April 26, 2018: Annual Review of Immunology
Makoto Konishi, Norihisa Shindo, Masataka Komiya, Kozo Tanaka, Takehiko Itoh, Toru Hirota
Separation of sister chromatids is a drastic and irreversible step in the cell cycle. The key biochemistry behind this event is the proteolysis mediated by the ubiquitin ligase called the anaphase promoting complex, or APC/C. Securin and cyclin B1 are the two established substrates for APC/C whose degradation releases separase and inactivates cyclin B1-dependent kinase 1 (cdk1), respectively, at the metaphase-to-anaphase transition. In this study, we have combined biochemical quantifications with mathematical simulations to characterize the kinetic regulation of securin and cyclin B1, in the cytoplasmic and chromosomal compartments, and found that they are differentially distributed and degraded with different rates...
2018: Biomedical Research
Agnieszka Hareza, Magda Bakun, Bianka Świderska, Małgorzata Dudkiewicz, Alicja Koscielny, Anna Bajur, Jacek Jaworski, Michał Dadlez, Krzysztof Pawłowski
Many kinases are still 'orphans,' which means knowledge about their substrates, and often also about the processes they regulate, is lacking. Here, DIA1/C3orf58, a member of a novel predicted kinase-like family, is shown to be present in the endoplasmic reticulum and to influence trafficking via the secretory pathway. Subsequently, DIA1 is subjected to phosphoproteomics analysis to cast light on its signalling pathways. A liquid chromatography-tandem mass spectrometry proteomic approach with phosphopeptide enrichment is applied to membrane fractions of DIA1-overexpressing and control HEK293T cells, and phosphosites dependent on the presence of DIA1 are elucidated...
2018: PeerJ
Shangyu Hong, Wei Song, Peter-James H Zushin, Bingyang Liu, Mark P Jedrychowski, Amir I Mina, Zhaoming Deng, Dimitrije Cabarkapa, Jessica A Hall, Colin J Palmer, Hassan Aliakbarian, John Szpyt, Steven P Gygi, Ali Tavakkoli, Lydia Lynch, Norbert Perrimon, Alexander S Banks
OBJECTIVE: The inappropriate release of free fatty acids from obese adipose tissue stores has detrimental effects on metabolism, but key molecular mechanisms controlling FFA release from adipocytes remain undefined. Although obesity promotes systemic inflammation, we find activation of the inflammation-associated Mitogen Activated Protein kinase ERK occurs specifically in adipose tissues of obese mice, and provide evidence that adipocyte ERK activation may explain exaggerated adipose tissue lipolysis observed in obesity...
March 29, 2018: Molecular Metabolism
Lev Litichevskiy, Ryan Peckner, Jennifer G Abelin, Jacob K Asiedu, Amanda L Creech, John F Davis, Desiree Davison, Caitlin M Dunning, Jarrett D Egertson, Shawn Egri, Joshua Gould, Tak Ko, Sarah A Johnson, David L Lahr, Daniel Lam, Zihan Liu, Nicholas J Lyons, Xiaodong Lu, Brendan X MacLean, Alison E Mungenast, Adam Officer, Ted E Natoli, Malvina Papanastasiou, Jinal Patel, Vagisha Sharma, Courtney Toder, Andrew A Tubelli, Jennie Z Young, Steven A Carr, Todd R Golub, Aravind Subramanian, Michael J MacCoss, Li-Huei Tsai, Jacob D Jaffe
Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP)...
April 10, 2018: Cell Systems
Sandra A Touati, Meghna Kataria, Andrew W Jones, Ambrosius P Snijders, Frank Uhlmann
The cell division cycle culminates in mitosis when two daughter cells are born. As cyclin-dependent kinase (Cdk) activity reaches its peak, the anaphase-promoting complex/cyclosome (APC/C) is activated to trigger sister chromatid separation and mitotic spindle elongation, followed by spindle disassembly and cytokinesis. Degradation of mitotic cyclins and activation of Cdk-counteracting phosphatases are thought to cause protein dephosphorylation to control these sequential events. Here, we use budding yeast to analyze phosphorylation dynamics of 3,456 phosphosites on 1,101 proteins with high temporal resolution as cells progress synchronously through mitosis...
April 12, 2018: EMBO Journal
Peng Chen, Ru Li, Ruiyang Zhou
Cytoplasmic male sterility (CMS) is widely used in plant breeding and represents a perfect model to understand cyto-nuclear interactions and pollen development research. Protein phosphorylation is ubiquitous and is involved in the regulation of diverse cellular processes. To reveal the possible mechanism of CMS and pollen development in kenaf, we performed an iTRAQ-based comparative phosphoproteome analysis in the anthers of a CMS line and wild-type plant (Wt). Whole transcriptome unigenes of kenaf as the reference genome, we identified a total of 3045 phosphorylated sites on 1640 peptides corresponding to 974 unique proteins...
April 11, 2018: Amino Acids
Kimberly Baumgardner, Connie Lin, Richard A Firtel, Jesus Lacal
The migration of cells according to a diffusible chemical signal in their environment is called chemotaxis, and the slime mold Dictyostelium discoideum is widely used for the study of eukaryotic chemotaxis. Dictyostelium must sense chemicals, such as cAMP, secreted during starvation to move toward the sources of the signal. Previous work demonstrated that the gskA gene encodes the Dictyostelium homologue of glycogen synthase kinase 3 (GSK3), a highly conserved serine/threonine kinase, which plays a major role in the regulation of Dictyostelium chemotaxis...
April 6, 2018: Environmental Microbiology
Kristan H Cleveland, Steven Yeung, Kevin M Huang, Sherry Liang, Bradley T Andresen, Ying Huang
Recent studies suggest that the β-blocker drug carvedilol prevents skin carcinogenesis but the mechanism is unknown. Carvedilol is one of a few β-blockers identified as biased agonist based on an ability to promote β-arrestin-mediated processes such as ERK phosphorylation. To understand the role of phosphoproteomic signaling in carvedilol's anticancer activity, the mouse epidermal JB6 P+ cells treated with EGF, carvedilol or their combination were analyzed using the Phospho Explorer Antibody Array containing 1318 site-specific and phospho-specific antibodies of over 30 signaling pathways...
April 6, 2018: Molecular Carcinogenesis
Christine Lam, Ian D Ferguson, Margarette C Mariano, Yu-Hsiu T Lin, Megan Murnane, Hui Liu, Geoffrey A Smith, Sandy W Wong, Jack Taunton, Jun O Liu, Constantine S Mitsiades, Byron C Hann, Blake T Aftab, Arun P Wiita
The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models...
April 5, 2018: Haematologica
Xiaomo Wu, Xiaohua Xing, Djameel Dowlut, Yongyi Zeng, Jingfeng Liu, Xiaolong Liu
Protein phosphorylation is a post-translational modification that is involved in the regulation of all major biological processes in cells. As a rapid and reversible means to modulate protein activity and transduce signals, aberrant protein phosphorylation is implicated in the onset and progression of most cancer types. Therefore, pharmacological inhibitors against protein kinases are highly pursued therapeutic approaches for treating cancer. Phosphoproteomics has become an important approach for investigating protein phosphorylation, and it is a technique that provides measurements of kinase pathway activation and the circuitry of signalling networks with both spatial and temporal resolution...
April 2, 2018: Journal of Proteomics
Hua Ni, Weiwei Fan, Chaolong Li, Qianqian Wu, Hongfen Hou, Dan Hu, Feng Zheng, Xuhui Zhu, Changjun Wang, Xiangrong Cao, Zhu-Qing Shao, Xiuzhen Pan
Streptococcus suis serotype 2 is an important swine pathogen and an emerging zoonotic agent that causes severe infections. Recent studies have reported a eukaryotic-like Ser/Thr protein kinase (STK) gene and characterized its role in the growth and virulence of different S. suis 2 strains. In the present study, phosphoproteomic analysis was adopted to identify substrates of the STK protein. Seven proteins that were annotated to participate in different cell processes were identified as potential substrates, which suggests the pleiotropic effects of stk on S...
2018: Frontiers in Cellular and Infection Microbiology
Ryan Peckner, Samuel A Myers, Alvaro Sebastian Vaca Jacome, Jarrett D Egertson, Jennifer G Abelin, Michael J MacCoss, Steven A Carr, Jacob D Jaffe
Mass spectrometry with data-independent acquisition (DIA) is a promising method to improve the comprehensiveness and reproducibility of targeted and discovery proteomics, in theory by systematically measuring all peptide precursors in a biological sample. However, the analytical challenges involved in discriminating between peptides with similar sequences in convoluted spectra have limited its applicability in important cases, such as the detection of single-nucleotide polymorphisms (SNPs) and alternative site localizations in phosphoproteomics data...
April 2, 2018: Nature Methods
Christoph Taumer, Lena Griesbaum, Alen Kovacevic, Boumediene Soufi, Nicolas C Nalpas, Boris Macek
Increasing number of studies report the relevance of protein Ser/Thr/Tyr phosphorylation in bacterial physiology, yet the analysis of this type of modification in bacteria still presents a considerable challenge. Unlike in eukaryotes, where tens of thousands of phosphorylation events likely occupy more than two thirds of the proteome, the abundance of protein phosphorylation is much lower in bacteria. Even the state-of-the-art phosphopeptide enrichment protocols fail to remove the high background of abundant unmodified peptides, leading to low signal intensity and undersampling of phosphopeptide precursor ions in consecutive data-dependent MS runs...
March 29, 2018: Journal of Proteomics
Veronika Suni, Tomi Suomi, Tomoya Tsubosaka, Susumu Y Imanishi, Laura L Elo, Garry L Corthals
Motivation: Mass spectrometry combined with enrichment strategies for phosphorylated peptides has been successfully employed for two decades to identify sites of phosphorylation. However, unambiguous phosphosite assignment is considered challenging. Given that site-specific phosphorylation events function as different molecular switches, validation of phosphorylation sites is of utmost importance. In our earlier study we developed a method based on simulated phosphopeptide spectral libraries, which enables highly sensitive and accurate phosphosite assignments...
March 27, 2018: Bioinformatics
Lian Yi, Tujin Shi, Marina A Gritsenko, Chi-Yuet X'avia Chan, Thomas L Fillmore, Becky M Hess, Adam C Swensen, Tao Liu, Richard D Smith, H Steven Wiley, Wei-Jun Qian
Large-scale phosphoproteomics with coverage of over 10,000 sites of phosphorylation have now been routinely achieved with advanced mass spectrometry (MS)-based workflows. However, accurate targeted MS-based quantification of phosphorylation dynamics, an important direction for gaining quantitative understanding of signaling pathways or networks, has been much less investigated. Herein, we report an assessment of the targeted workflow in the context of signal transduction pathways, using the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) pathway as our model...
April 3, 2018: Analytical Chemistry
Manshun Liu, Yanchao Wei, Xin Li, Siew Young Quek, Jing Zhao, Huazhen Zhong, Dequan Zhang, Yongfeng Liu
During the conversion of muscle to meat, protein phosphorylation can regulate various biological processes that have important effects on meat quality. To investigate the phosphorylation pattern of protein on rigor mortis, goat longissimus thoracis and external intercostals were classified into two groups (high quality and low quality), and meat quality was evaluated according to meat quality attributes (Warner-Bratzler shear force, Color, pH and drip loss). A quantitative mass spectrometry-based phosphoproteomic study was conducted to analyze the caprine muscle at 12h postmortem applying the TiO2 -SIMAC-HILIC (TiSH) phosphopeptide enrichment strategy...
January 2, 2018: Meat Science
Zhen Yang, Xuetong Wang, Wensheng Xu, Mian Zhou, Yuanxing Zhang, Yue Ma, Qiyao Wang
Type VI secretion systems (T6SSs) are multi-protein secretory nano-machines that mediate inter-bacterial competition. Vibrio alginolyticus is an abundant gram-negative marine bacterium that efficiently kills other bacteria with its T6SS2. The V. alginolyticus T6SS2 gene cluster encodes a phosphatase, PppA, and a type II membrane-spanning Hanks-type threonine kinase, PpkA2, which have been implicated in the activation of T6S. Meanwhile, T6SS2 gene expression is under the control of quorum sensing. However, the role of PppA in T6SS2 activity is unclear...
April 2018: Microbiological Research
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