Abstract
Engagement of the B cell antigen receptor initiates two concurrent processes, signaling and receptor internalization. While both are required for normal humoral immune responses, the relationship between these two processes is unknown. Herein, we demonstrate that following receptor ligation, a small subpopulation of B cell antigen receptors are inductively phosphorylated and selectively retained at the cell surface where they can serve as scaffolds for the assembly of signaling molecules. In contrast, the larger population of non-phosphorylated receptors is rapidly endocytosed. Each receptor can undergo only one of two mutually exclusive fates because the tyrosine-based motifs that mediate signaling when phosphorylated mediate internalization when not phosphorylated. Mathematical modeling indicates that the observed competition between receptor phosphorylation and internalization enhances signaling responses to low avidity ligands.
Highlights
The recognition of polyvalent antigens by the B cell antigen receptor (BCR) initiates a complex web of signaling events that determine cellular responses [1]
The Tyrosines within Iga Are Required for Internalization Tyrosine-based motifs consisting of YXX/ are well described binding sites for adaptor protein (AP)-2, and other adaptors, which mediate receptor endocytosis [45]
To simplify our initial analysis, we chose to examine the cytosolic tail of Iga in isolation as a chimera with the extracellular and transmembrane domains of human platelet derived growth factor receptor (PDGFR) [47,48]
Summary
The recognition of polyvalent antigens by the B cell antigen receptor (BCR) initiates a complex web of signaling events that determine cellular responses [1]. Polyvalent antigen induces the rapid internalization of engaged receptors which is required for the effective presentation of antigen-derived MHC class II restricted peptides to T cells [2]. As important as these two processes are, the relationships between them are poorly understood. Iga/Igb ITAMs serve to recruit and activate the tyrosine kinase Syk [9,10,11]. Syk phosphorylates BLNK ( termed BASH or SLP65) [19,20,21,22], a scaffolding molecule that is recruited to the BCR through a unique phosphorylated non-ITAM tyrosine in the Iga cytosolic tail [23,24]. BLNK coordinates the assembly and activation of a receptor-retained signalsome containing PLCc2, Vav, Btk, Nck, and Grb2 [25]
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