Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation.
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.
Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Gina J
GJ
Fiala
Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Iga
I
Janowska
Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Fabiola
F
Prutek
Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Institute of Immunology, University Hospital Ulm, 89081 Ulm, Germany.
Elias
E
Hobeika
Center of Synaptic Neuroscience, Italian Institute of Technology, 16163 Genova, Italy.
Annyesha
A
Satapathy
Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Adrian
A
Sprenger
Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Thomas
T
Plum
Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Maximilian
M
Seidl
Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Jörn
J
Dengjel
Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Michael
M
Reth
Center of Synaptic Neuroscience, Italian Institute of Technology, 16163 Genova, Italy.
Fabrizia
F
Cesca
Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany.
Tilman
T
Brummer
Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany wolfgang.schamel@biologie.uni-freiburg.de susana-minguet@biologie.uni-freiburg.de.
Susana
S
Minguet
Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany Centre for Biological Signaling Studies (BIOSS), Spemann Graduate School of Biology and Medicine (SGBM), Centre of Chronic Immunodeficiency (CCI), Department of Dermatology, Center for Biological Systems Analysis (ZBSA), Institute of Molecular Medicine and Cell Research, Comprehensive Cancer Centre Freiburg, and Institute of Pathology, University Medical Center Freiburg, University of Freiburg, 79104 Freiburg, Germany wolfgang.schamel@biologie.uni-freiburg.de susana-minguet@biologie.uni-freiburg.de.
Wolfgang W A
WW
Schamel
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D001854:Bone Marrow Cells / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D007072:Immunoglobulin D / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051966:Phospholipase C gamma / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D013154:Spleen / Q000166:cytology
D007072:Immunoglobulin D; D007075:Immunoglobulin M; C544017:Kidins220 protein, mouse; D008565:Membrane Proteins; D011947:Receptors, Antigen, B-Cell; D051966:Phospholipase C gamma; D002118:Calcium