title: STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development.
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.
authors: Department of Medicine, Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, University of California at San Francisco, San Francisco, California, USA.
authors: Andre
authors: A
authors: Limnander
authors: Philippe
authors: P
authors: Depeille
authors: Tanya S
authors: TS
authors: Freedman
authors: Jen
authors: J
authors: Liou
authors: Michael
authors: M
authors: Leitges
authors: Tomohiro
authors: T
authors: Kurosaki
authors: Jeroen P
authors: JP
authors: Roose
authors: Arthur
authors: A
authors: Weiss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D015220:Calcium Channels; D002460:Cell Line; D004789:Enzyme Activation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology*; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000276:immunology*; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000276:immunology; D051745:Protein Kinase C-delta / Q000276:immunology*; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D020662:Guanine Nucleotide Exchange Factors; D008562:Membrane Glycoproteins; C112278:Rasgrp1 protein, mouse; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases