1. STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development
- Author
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Limnander, Andre, Depeille, Philippe, Freedman, Tanya S, Liou, Jen, Leitges, Michael, Kurosaki, Tomohiro, Roose, Jeroen P, and Weiss, Arthur
- Subjects
B-Lymphocytes ,Membrane Glycoproteins ,1.1 Normal biological development and functioning ,Knockout ,Immunoblotting ,Immunology ,Apoptosis ,Inbred C57BL ,Flow Cytometry ,Cell Line ,Enzyme Activation ,Mice ,Protein Kinase C-delta ,Gene Expression Regulation ,Underpinning research ,Animals ,Guanine Nucleotide Exchange Factors ,Developmental ,Generic health relevance ,Calcium Channels ,Stromal Interaction Molecule 1 ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Signal Transduction - Abstract
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.
- Published
- 2011