SLP-76 is recruited to CD22 and dephosphorylated by SHP-1, thereby regulating B cell receptor-induced c-Jun N-terminal kinase activation.
Despite the important role in the development and activation of T cells, NK cells, mast cells, and macrophages, the expression and function of SLP-76 in B cells have been largely unknown. Here we demonstrate that SLP-76 is expressed in all mouse B cell lines tested and in normal splenic B cells, and serves as an SHP-1 substrate. Dephosphorylation of SLP-76 by SHP-1 inhibits its association with Nck, down-regulating c-Jun N-terminal kinase (JNK) activation and exerting a positive effect on apoptosis. Knockdown of SLP-76 in WEHI-231 cells by small interfering RNA attenuated JNK activation, but showed little effects on extracellular signal-regulated kinase (ERK) or p38 activation. Although WEHI-231 does not express linker for activation of T cells (LAT), SLP-76 localizes in membrane fraction, which increases following B cell receptor (BCR) cross-linking. Further analyses revealed that SLP-76 complexed with Gads is associated with tyrosine-phosphorylated CD22 through the SH2 domains of SLP-76 and Gads. Given that SHP-1 binds to CD22 upon BCR ligation, our findings suggest that dephosphorylation of SLP-76 recruited to CD22 by SHP-1 inhibits BCR-induced JNK activation, dictating apoptosis.
Mizuno
Kazuya
K
Department of Immunology and Signal Transduction, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan. kzmizuno@tmin.ac.jp
Tagawa
Yuko
Y
Watanabe
Noriyuki
N
Ogimoto
Mami
M
Yakura
Hidetaka
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; C498726:Mona protein, mouse; C078332:Nck protein; D015513:Oncogene Proteins; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D051918:Sialic Acid Binding Ig-like Lectin 2; D014443:Tyrosine; D048031:JNK Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse