| First Author | Limnander A | Year | 2011 |
| Journal | Nat Immunol | Volume | 12 |
| Issue | 5 | Pages | 425-33 |
| PubMed ID | 21441934 | Mgi Jnum | J:171921 |
| Mgi Id | MGI:5002403 | Doi | 10.1038/ni.2016 |
| Citation | Limnander A, et al. (2011) STIM1, PKC-delta and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nat Immunol 12(5):425-33 |
| abstractText | 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-delta (PKC-delta) 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-delta-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. |
