Differential use of BTK and PLC in FcεRI- and KIT-mediated mast cell activation: A marginal role of BTK upon KIT activation
| Autor: | Thomas Wilhelm, Carolin N. Zorn, Anne Simonowski, Michael Huber, Pardes Habib |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine MAP Kinase Kinase 4 p38 mitogen-activated protein kinases Stem cell factor p38 Mitogen-Activated Protein Kinases Mice 03 medical and health sciences chemistry.chemical_compound Piperidines immune system diseases hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase Animals Bruton's tyrosine kinase Mast Cells Phosphorylation Molecular Biology Cells Cultured 030102 biochemistry & molecular biology biology Phospholipase C gamma Receptors IgE Chemistry Kinase Adenine Degranulation Tyrosine phosphorylation Cell Biology Cell biology Mice Inbred C57BL Proto-Oncogene Proteins c-kit Pyrimidines 030104 developmental biology biology.protein Cytokines Pyrazoles Calcium Female Signal transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1867:118622 |
| ISSN: | 0167-4889 |
| DOI: | 10.1016/j.bbamcr.2019.118622 |
| Popis: | In mast cells (MCs), the TEC family kinase (TFK) BTK constitutes a central regulator of antigen (Ag)-triggered, FceRI-mediated PLCγ phosphorylation, Ca2+ mobilization, degranulation, and pro-inflammatory cytokine production. Less is known about the function of BTK in the context of stem cell factor (SCF)-induced KIT signaling. In bone marrow-derived MCs (BMMCs), Ag stimulation caused intense phosphorylation of BTK at Y551 in its active center and at Y223 in its SH3-domain, whereas in response to SCF only Y223 was significantly phosphorylated. Further data using the TFK inhibitor Ibrutinib indicated that BTK Y223 is phosphorylated by a non-BTK TFK upon SCF stimulation. In line, SCF-induced PLCγ1 phosphorylation was stronger attenuated by Ibrutinib than by BTK deficiency. Subsequent pharmacological analysis of PLCγ function revealed a total block of SCF-induced Ca2+ mobilization by PLC inhibition, whereas only the sustained phase of Ca2+ flux was curtailed in Ag-stimulated BMMCs. Despite this severe stimulus-dependent difference in inducing Ca2+ mobilization, PLCγ inhibition suppressed Ag- and SCF-induced degranulation and pro-inflammatory cytokine production to comparable extents, suggesting involvement of additional TFK(s) or PLCγ-dependent signaling components. In addition to PLCγ, the MAPKs p38 and JNK were activated by Ag in a BTK-dependent manner; this was not observed upon SCF stimulation. Hence, FceRI and KIT employ different mechanisms for activating PLCγ, p38, and JNK, which might strengthen their cooperation regarding pro-inflammatory MC effector functions. Importantly, our data clearly demonstrate that analyzing BTK Y223 phosphorylation is not sufficient to prove BTK activation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect