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Berlin Brandenburg

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  • 1
    In: Molecular BioSystems, 2012, Vol.8(4), pp.1100-1107
    Description: In the last decade, large-scale mass spectrometry-based phosphoproteomic studies of receptor tyrosine kinases (RTKs) have generated a compendium of signalling networks that are activated downstream of these receptors. In this article, a brief summary of previous phosphoproteomic studies on epidermal growth factor receptor (EGFR) signalling will be presented together with a perspective on the importance for the field to keep pace with new advances in RTK biology. Using examples drawn primarily from studies on the EGFR, c-Met and Flt3 receptors, areas in RTK biology which will greatly benefit from the power of phosphoproteomics will be discussed, including (a) validating oncogenic RTK mutants identified in cancer genome sequencing efforts, (b) spatial RTK signalling networks and (c) understanding crosstalk and co-activation between members of the RTK superfamily.
    Keywords: Biology;
    ISSN: 1742-206X
    E-ISSN: 1742-2051
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  • 2
    Language: English
    In: Nature, May 21, 2009, Vol.459(7245), p.336(2)
    Keywords: Proteomics -- Analysis ; Skin Cancer -- Risk Factors ; Skin Cancer -- Prognosis ; Gene Mutation -- Analysis ; Melanoma -- Health Aspects
    ISSN: 0028-0836
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  • 3
    Language: English
    In: Journal of Molecular Biology, 16 June 2017, Vol.429(12), pp.1767-1786
    Description: Despite the recent approval of third-generation therapies, overcoming resistance to epidermal growth factor receptor (EGFR) inhibitors remains a major challenge in non-small cell lung cancer. Conceptually, synthetic lethality holds the promise of identifying non-intuitive targets for tackling both acquired and intrinsic resistance in this setting. However, translating these laboratory findings into effective clinical strategies continues to be elusive. Here, we provide an overview of the synthetic lethal approaches that have been employed to study EGFR inhibitor resistance and review the oncogene and non-oncogene signalling mechanisms that have thus far been unveiled by synthetic lethality screens. We highlight the potential challenges associated with progressing these discoveries into the clinic including context dependency, signalling plasticity, and tumour heterogeneity, and we offer a perspective on emerging network biology and computational solutions to exploit these phenomena for cancer therapy and biomarker discovery. We conclude by presenting a number of tangible steps to bolster our understanding of fundamental synthetic lethality mechanisms and advance these findings beyond the confines of the laboratory.
    Keywords: Non-Small Cell Lung Cancer ; Synthetic Lethality ; Epidermal Growth Factor Receptor ; Drug Resistance ; Network Biology ; Biology ; Chemistry
    ISSN: 0022-2836
    E-ISSN: 1089-8638
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  • 4
    Language: English
    In: Cellular and Molecular Life Sciences, 2014, Vol.71(17), pp.3269-3279
    Description: The discoidin domain receptors (DDRs) are collagen-binding receptor tyrosine kinases that have been implicated in a number of fundamental biological processes ranging from growth and development to immunoregulation. In this review, we examine how recent proteomic technologies have enriched our understanding of DDR signaling mechanisms. We provide an overview on the use of large-scale proteomic profiling and chemical proteomics to reveal novel insights into DDR therapeutics, signaling networks, and receptor crosstalk. A perspective of how proteomics may be harnessed to answer outstanding fundamental questions including the dynamic regulation of receptor activation kinetics is presented. Collectively, these studies present an emerging molecular portrait of these unique receptors and their functional role in health and disease.
    Keywords: Discoidin domain receptors ; Collagen ; Cell signaling ; Proteomics ; Mass spectrometry
    ISSN: 1420-682X
    E-ISSN: 1420-9071
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  • 5
    Language: English
    In: Expert Review of Anticancer Therapy, 02 January 2017, Vol.17(1), pp.1-3
    Keywords: Swi/Snf ; Smarcb1 ; Receptor Tyrosine Kinase ; Tyrosine Kinase Inhibitor ; Cancer ; Signal Transduction ; Medicine
    ISSN: 1473-7140
    E-ISSN: 1744-8328
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  • 6
    Language: English
    In: European Journal of Cancer, March 2018, Vol.92, pp.33-39
    Description: Recent randomised phase II trial data have indicated that the addition of olaratumab, a novel monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRα), to doxorubicin confers an unprecedented improvement in overall survival to patients with anthracycline-naïve advanced soft tissue sarcoma. However, this result was disproportionate with progression-free survival and response rate, and consequently there are unanswered questions regarding the precise mechanism of action of olaratumab. While preclinical data show that olaratumab specifically inhibits PDGFRα-mediated oncogenic signalling with attendant anti-tumour effects, a lack of correlation between pharmacodynamics markers of PDGFRα inhibition and clinical benefit from olaratumab suggest other mechanisms beyond modulation of downstream PDGFRα molecular pathways. Proposed mechanisms of olaratumab activity include engagement of anti-tumour immune responses and alterations of the tumour stroma, but these require further evaluation. Meanwhile, the drug-specific contribution of cytotoxic agents to olaratumab-containing combinations has yet to be characterised. Ongoing and future preclinical and translational studies, coupled with the anticipated results of a phase III trial that has completed enrolment, should provide greater insight into the efficacy and mode of action of olaratumab in soft tissue sarcomas.
    Keywords: Olaratumab ; Soft Tissue Sarcoma ; Pdgfrα ; Therapeutic Antibody ; Doxorubicin ; Medicine
    ISSN: 0959-8049
    E-ISSN: 1879-0852
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  • 7
    Language: English
    In: Nature, 21 May 2009, Vol.459(7245), pp.336-7
    Description: Using an in vitro model system that is thought to mimic the way that melanoma cells spread through patients' bodies, the authors demonstrate that BRAF can stimulate melanoma-cell invasion by inducing FAM129B phosphorylation by ERK. Furthermore, the authors' screen identifies many proteins with acidic...
    Keywords: Melanoma -- Metabolism ; Proto-Oncogene Proteins B-Raf -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 8
    Language: English
    In: PloS one, 2015, Vol.10(3), pp.e0121143
    Description: Peach Prunus persica (L.) Batsch is self-compatible and largely self-fertile, but under greenhouse conditions pollinators must be introduced to achieve good fruit set and quality. Because little work has been done to assess the effectiveness of different pollinators on peach trees under greenhouse conditions, we studied 'Okubo' peach in greenhouse tunnels near Beijing between 2012 and 2014. We measured pollen deposition, pollen-tube growth rates, ovary development, and initial fruit set after the flowers were visited by either of two managed pollinators: bumblebees, Bombus patagiatus Nylander, and honeybees, Apis mellifera L. The results show that B. patagiatus is more effective than A. mellifera as a pollinator of peach in greenhouses because of differences in two processes. First, B. patagiatus deposits more pollen grains on peach stigmas than A. mellifera, both during a single visit and during a whole day of open pollination. Second, there are differences in the fertilization performance of the pollen deposited. Half of the flowers visited by B. patagiatus are fertilized 9-11 days after bee visits, while for flowers visited by A. mellifera, half are fertilized 13-15 days after bee visits. Consequently, fruit development is also accelerated by bumblebees, showing that the different pollinators have not only different pollination efficiency, but also influence the subsequent time course of fertilization and fruit set. Flowers visited by B. patagiatus show faster ovary growth and ultimately these flowers produce more fruit. Our work shows that pollinators may influence fruit production beyond the amount of pollen delivered. We show that managed indigenous bumblebees significantly outperform introduced honeybees in increasing peach initial fruit set under greenhouse conditions.
    Keywords: Pollination ; Bees -- Physiology ; Prunus -- Physiology
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2012, Vol.7(12), p.e52209
    Description: The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that bind to and are activated by collagens. Similar to collagen-binding β1 integrins, the DDRs bind to specific motifs within the collagen triple helix. However, these two types of collagen receptors recognize distinct collagen sequences. While GVMGFO (O is hydroxyproline) functions as a major DDR binding motif in fibrillar collagens, integrins bind to sequences containing Gxx'GEx". The DDRs are thought to regulate cell adhesion, but their roles have hitherto only been studied indirectly. In this study we used synthetic triple-helical collagen-derived peptides that incorporate either the DDR-selective GVMGFO motif or integrin-selective motifs, such as GxOGER and GLOGEN, in order to selectively target either type of receptor and resolve their contributions to cell adhesion. Our data using HEK293 cells show that while cell adhesion to collagen I was completely inhibited by anti-integrin blocking antibodies, the DDRs could mediate cell attachment to the GVMGFO motif in an integrin-independent manner. Cell binding to GVMGFO was independent of DDR receptor signalling and occurred with limited cell spreading, indicating that the DDRs do not mediate firm adhesion. However, blocking the interaction of DDR-expressing cells with collagen I via the GVMGFO site diminished cell adhesion, suggesting that the DDRs positively modulate integrin-mediated cell adhesion. Indeed, overexpression of the DDRs or activation of the DDRs by the GVMGFO ligand promoted α1β1 and α2β1 integrin-mediated cell adhesion to medium- and low-affinity integrin ligands without regulating the cell surface expression levels of α1β1 or α2β1. Our data thus demonstrate an adhesion-promoting role of the DDRs, whereby overexpression and/or activation of the DDRs leads to enhanced integrin-mediated cell adhesion as a result of higher integrin activation state.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: Methods in molecular biology (Clifton, N.J.), 2017, Vol.1636, pp.253-262
    Description: Robust isolation and identification of peptides phosphorylated at their tyrosine residues are key steps in deciphering complex signaling networks governed by protein tyrosine kinases, including kinases involved in oncogenesis. Phosphotyrosine (pY)-containing peptides are commonly isolated from cellular lysates by means of antibody and/or metal affinity-based enrichment followed by their identification by mass spectrometry. Herein, we describe robust two-stage isolation of phosphotyrosine peptides and mass spectrometry-aided identification of phosphosites to characterize basal signaling networks in unstimulated non-small cell lung cancer (NSCLC) cell lines.
    Keywords: Anti-Phosphotyrosine Antibodies ; Imac ; Immunoprecipitation ; Lung Cancer ; Mass Spectrometry ; Phosphotyrosine ; Protein Phosphorylation ; Tyrosine Kinases ; Proteome ; Proteomics ; Signal Transduction ; Lung Neoplasms -- Metabolism ; Phosphoproteins -- Metabolism ; Phosphotyrosine -- Metabolism
    E-ISSN: 1940-6029
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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