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The X-linked lymphoproliferative syndrome gene product SAP regulates B cell function through the FcγRIIB receptor
- Source :
- Cellular Signalling. 20:1960-1967
- Publication Year :
- 2008
- Publisher :
- Elsevier BV, 2008.
-
Abstract
- X-linked lympho-proliferative (XLP) is an immunodeficiency condition caused by mutation or deletion of the gene encoding the adaptor protein SAP/SH2D1A. Besides defects in T cell and NK cell function and an absence of NKT cells, XLP can also manifest as lymphomas resulting primarily from uncontrolled B cell proliferation upon acute infection by Epstein-Barr virus. While it has been demonstrated that SAP regulates the functions of T cells and NK cells through the SLAM family of immunoreceptors, its role in B cells has not been defined. Here we show that SAP forms a ternary complex with the kinase Lyn and the inhibitory IgG Fc receptor FcgammaRIIB to regulate B cell proliferation and survival. SAP binds directly and simultaneously to the Lyn SH3 domain and an Immuno-receptor Tyrosine-based Inhibitory Motif (ITIM) in FcgammaRIIB, resulting in the activation of the latter. Moreover, SAP associates with FcgammaRIIB in mouse splenic B cells and promotes its tyrosine phosphorylation. Expression of SAP in the A20 B cell line led to a marked reduction in Blnk phosphorylation, a decrease in Akt activation, and a near-complete ablation of phosphorylation of the MAP kinases Erk1/2, p38 and JNK upon colligation of FcgammaRIIB with the B cell receptor (BCR). In contrast, an XLP-causing SAP mutant was much less efficient in eliciting these effects in B cells. Furthermore, compared to A20 cells, SAP transfectants displayed a significantly reduced rate of proliferation and an increased sensitivity to activation-induced cell death. Collectively these data identify an intrinsic function for SAP in inhibitory signaling in B cells and suggests that SAP may play an important role in balancing positive versus negative immune responses.
- Subjects :
- Cell Survival
T cell
B-cell receptor
Fc receptor
Receptors, Antigen, B-Cell
Lymphocyte Activation
Cell Line
src Homology Domains
Mice
chemistry.chemical_compound
LYN
medicine
Animals
Humans
Signaling Lymphocytic Activation Molecule Associated Protein
Phosphorylation
Protein kinase B
B cell
Adaptor Proteins, Signal Transducing
Cell Proliferation
B-Lymphocytes
Cell Death
biology
Receptors, IgG
Intracellular Signaling Peptides and Proteins
Tyrosine phosphorylation
Cell Biology
Natural killer T cell
Lymphoproliferative Disorders
Cell biology
src-Family Kinases
medicine.anatomical_structure
chemistry
biology.protein
Mitogen-Activated Protein Kinases
Proto-Oncogene Proteins c-akt
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 08986568
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Cellular Signalling
- Accession number :
- edsair.doi.dedup.....2c3f12c91bfbd6890af542dd21a4d4f3