title: SAP binds to CD22 and regulates B cell inhibitory signaling and calcium flux.
abstract: The signaling lymphocyte activation molecule (SLAM)-associated protein (SAP or SH2D1A) is an important regulator of immune function which, when mutated or deleted, causes the X-linked lymphoproliferative syndrome (XLP). Because B cell lymphoma is a major phenotype of XLP, it is important to understand the function of SAP in B cells. Here we report that SAP is expressed endogenously in mouse splenic B cells, is inducibly expressed in the human BJAB cells, and co-localizes and interacts with CD22. We also show that SAP binding to the inhibitory immunoreceptor CD22 regulates calcium mobilization in B cells. Moreover, forced expression of SAP leads to constitutive CD22 tyrosine phosphorylation and decreased Ca(2+) response in B cells. Biochemical analysis reveals that, in response to IgM cross-linking, the phosphorylation of Syk, Blnk, or PLCgamma2 and their interactions with one another were either diminished or completely abolished in SAP-expressing cells compared to cells that lack SAP. Collectively our work identifies a novel role for SAP in B cells and extends its function to inhibitory immunoreceptor signaling and calcium mobilization.
authors.affiliation: Department of Biochemistry and the Siebens-Drake Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1. eostrakh@uwo.ca
authors.forename: Elena A
authors.initials: EA
authors.lastname: Ostrakhovitch
authors.forename: Yefu
authors.initials: Y
authors.lastname: Wang
authors.forename: Shawn S-C
authors.initials: SS
authors.lastname: Li
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology; D002051:Burkitt Lymphoma / Q000473:pathology; D020013:Calcium Signaling / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; C499569:Sh2d1a protein, mouse; D051918:Sialic Acid Binding Ig-like Lectin 2; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D011505:Protein-Tyrosine Kinases; D002945:Cisplatin