STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development

Andre Limnander, Philippe Depeille, Tanya S. Freedman, Jen Liou, Michael Leitges, Tomohiro Kurosaki, Jeroen P. Roose, Arthur Weiss

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

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 Ca2+-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 Ca2+ sensor STIM1, which controls the magnitude of Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)425-433
Number of pages9
JournalNature immunology
Volume12
Issue number5
DOIs
StatePublished - May 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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