Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 212, Issue 10, Pages 1693-1708Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20141271
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Funding
- German Research Foundation (DFG) through the Excellence Initiative [GSC-4, EXC294]
- Emmy-Noether Program of the DFG
- DFG [SFB1160, SFB746, TRR130]
- ERC [32297]
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B cell antigen receptor (BCR) signaling is critical for B cell development and activation. Using mass spectrometry, we identified a protein kinase D-interacting substrate of 220 kD (Kidins220)/ankyrin repeat-rich membrane-spanning protein (ARMS) as a novel interaction partner of resting and stimulated BCR. Upon BCR stimulation, the interaction increases in a Src kinase-independent manner. By knocking down Kidins220 in a B cell line and generating a conditional B cell-specific Kidins220 knockout (B-KO) mouse strain, we show that Kidins220 couples the BCR to PLC gamma 2, Ca2+, and extracellular signal-regulated kinase (Erk) signaling. Consequently, BCR-mediated B cell activation was reduced in vitro and in vivo upon Kidins220 deletion. Furthermore, B cell development was impaired at stages where pre-BCR or BCR signaling is required. Most strikingly, lambda light chain-positive B cells were reduced sixfold in the B-KO mice, genetically placing Kidins220 in the PLC gamma 2 pathway. Thus, our data indicate that Kidins220 positively regulates pre-BCR and BCR functioning.
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