Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival
| Autor: | Jürgen Wienands, Hanibal Bohnenberger, Jennifer Hüllein, Federico Comoglio, Sebastian Mohr, Philipp Ströbel, Carmen Doebele, Henning Urlaub, Michael Engelke, Michael A. Rieger, Thorsten Zenz, Jasmin Corso, Thomas Oellerich, Kuan-Ting Pan, Roland Walter, Christof Lenz, Mikolaj Slabicki, Hubert Serve |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell Survival B-cell receptor Receptors Antigen B-Cell Biology 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Cell Line Tumor medicine Humans Phosphorylation B-Lymphocytes Multidisciplinary Effector Kinase breakpoint cluster region Phosphoproteomics Biological Sciences medicine.disease Burkitt Lymphoma 3. Good health Lymphoma Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Burkitt's lymphoma Protein Processing Post-Translational Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeleton-related processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments. |
| Databáze: | OpenAIRE |
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