Stim1, PKCδ and RasGRP proteins set a threshold for pro-apoptotic Erk signaling during B cell development
| Autor: | Limnander, Andre, Depeille, Philippe, Freedman, Tanya S., Liou, Jen, Leitges, Michael, Kurosaki, Tomohiro, Roose, Jeroen P., Weiss, Arthur |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Mice
Knockout B-Lymphocytes Membrane Glycoproteins Immunoblotting Gene Expression Regulation Developmental Apoptosis Flow Cytometry Article Cell Line Enzyme Activation Mice Inbred C57BL Mice Protein Kinase C-delta Animals Guanine Nucleotide Exchange Factors Calcium Channels Stromal Interaction Molecule 1 Phosphorylation Extracellular Signal-Regulated MAP Kinases Signal Transduction |
| Zdroj: | Nature immunology |
| ISSN: | 1529-2916 1529-2908 |
| Popis: | Clonal deletion of autoreactive B cells is crucial for the prevention of autoimmunity, but the signaling mechanisms that regulate this checkpoint remain undefined. Here we characterize a previously unrecognized Ca(2+)-driven pathway for activation of the kinase Erk, which was proapoptotic and biochemically distinct from Erk activation induced by diacylglycerol (DAG). This pathway required protein kinase C-δ (PKC-δ) and the guanine nucleotide-exchange factor RasGRP and depended on the concentration of the Ca(2+) sensor STIM1, which controls the magnitude of Ca(2+) entry. Developmental regulation of these proteins was associated with selective activation of the pathway in B cells prone to negative selection. This checkpoint was impaired in PKC-δ-deficient mice, which developed B cell autoimmunity. Conversely, overexpression of STIM1 conferred a competitive disadvantage to developing B cells. Our findings establish Ca(2+)-dependent Erk signaling as a critical proapoptotic pathway that mediates the negative selection of B cells. |
| Databáze: | OpenAIRE |
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