Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation

J Exp Med. 2015 Sep 21;212(10):1693-708. doi: 10.1084/jem.20141271. Epub 2015 Aug 31.

Abstract

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 PLCγ2, Ca(2+), 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, λ light chain-positive B cells were reduced sixfold in the B-KO mice, genetically placing Kidins220 in the PLCγ2 pathway. Thus, our data indicate that Kidins220 positively regulates pre-BCR and BCR functioning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / physiology*
  • Bone Marrow Cells / metabolism
  • Calcium / metabolism
  • Immunoglobulin D / metabolism
  • Immunoglobulin M / metabolism
  • Lymphocyte Activation
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phospholipase C gamma / metabolism
  • Receptors, Antigen, B-Cell / metabolism*
  • Spleen / cytology

Substances

  • Immunoglobulin D
  • Immunoglobulin M
  • Kidins220 protein, mouse
  • Membrane Proteins
  • Receptors, Antigen, B-Cell
  • Phospholipase C gamma
  • Calcium