Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer
| Autor: | Zhengshan Chen, Maike Buchner, Kadriye Nehir Cosgun, Pauline Soulas-Sprauel, Nora Heisterkamp, Veronika Ecker, Lars Klemm, Anne Marie Knapp, Joo Y. Song, Friedemann Kiefer, Supraja Saravanakumar, Markus Müschen, Thierry Martin, Mark Robinson, Hassan Jumaa, Vu N. Ngo, Dana Ghergus, Tanya Siddiqi, Kohei Kume, Laura Oksa, Mickaël Martin, Teresa Sadras, Jevon Cutler, Lili Wang, Janet Winchester, Eric Meffre, Gal Lenz, Wing C. Chan, Jürgen Ruland, Akhilesh Pandey |
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| Přispěvatelé: | Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tampere University, Clinical Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Lymphoma
B-Cell Chronic lymphocytic leukemia B-cell receptor Antigens CD19 Syk Receptors Antigen B-Cell Autoimmunity Biology Article 03 medical and health sciences Negative selection Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Neoplasms medicine Immune Tolerance Animals Humans Syk Kinase Molecular Biology B cell 030304 developmental biology 0303 health sciences B-Lymphocytes ZAP-70 Protein-Tyrosine Kinase Models Genetic NFATC Transcription Factors ZAP70 B cell selection breakpoint cluster region Cell Differentiation Cell Biology medicine.disease Neoplasm Proteins Enzyme Activation medicine.anatomical_structure Cell Transformation Neoplastic Cancer research Calcium 3111 Biomedicine 030217 neurology & neurosurgery [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Protein Binding Signal Transduction |
| Zdroj: | Molecular Cell Molecular Cell, Elsevier, 2021, 81 (10), ⟨10.1016/j.molcel.2021.03.043⟩ Mol Cell |
| ISSN: | 1097-2765 |
| Popis: | Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies. acceptedVersion |
| Databáze: | OpenAIRE |
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