REGULATORY FUNCTIONS OF THE ACTIN CYTOSKELETON IN B CELL RECEPTOR SIGNALING

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dc.contributor.advisorSong, Wenxiaen_US
dc.contributor.authorLiu, Chaohongen_US
dc.contributor.departmentCell Biology & Molecular Geneticsen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2013-10-04T05:31:51Z
dc.date.available2013-10-04T05:31:51Z
dc.date.issued2013en_US
dc.description.abstractThe binding of antigen (Ag) to the B cell receptor (BCR) induces the activation of intracellular signaling and the reorganization of the actin cytoskeleton. However, the function of actin reorganization and the mechanisms by which BCR signaling and actin reorganization is coupled have not been well studied. This thesis has investigated how BCR signaling regulates actin reorganization and how actin remodeling in turn influences BCR signalig. My studies show that the key stimulatory signaling molecule of the BCR, Bruton's tyrosine kinase (Btk), is critical for actin polymerization at the activation surface and BCR clustering and B cell spreading, events that are essential for signaling initiation and amplification. The key inhibitory signaling molecule, SH2-containing phosphatidylinositol-5 phasphatase (SHIP-1), is important for removal of F-actin from the activation surface, and actin-mediated B cell contraction and the formation of BCR central clusters. SHIP-1 suppresses actin polymerization by inhibiting Btk-dependent activation of Wiskott-Aldrich syndrome protein (WASP). These results suggest that BCR signaling can regulate B cell morphology and surface BCR clustering via modulationg actin dynamics. To understand the roles of actin reorganization in BCR signaling, I investigated the effects of gene knockout of the two actin regulators, WASP and its homolog, neuronal (N)-WASP. My results show that both WASP and N-WASP are required for optimal BCR clustering, B cell spreading, and BCR signaling, but they play distinct roles. WASP promotes actin polymerization, B cell spreading, BCR clustering, and signaling amplification, and N-WASP inhibits actin polymerization at the activation surface and promotes B cell contraction, BCR central cluster formation, and signaling attenuation. Importantly, B cell-specific N-WASP knockout causes increases in the levels of autoantibody. In addition, WASP and N-WASP negatively regulate each other, compete for Arp2/3, and are inversely regulated by Btk and SHIP-1. Taken together, these results demonstrate that the balance of stimulatory and inhibitory BCR signaling controls actin dynamics and organization through regulating the activities of WASP and N-WASP. Actin remodeling in turn amplifies BCR signaling activation or down regulation by modulating B cell morphlogy and the organization of surface BCRs.This research reveals a bidrectional feedback loop between BCR signaling and the actin cytoskeleton.en_US
dc.identifier.urihttp://hdl.handle.net/1903/14538
dc.subject.pqcontrolledImmunologyen_US
dc.subject.pquncontrolledactinen_US
dc.subject.pquncontrolledB cellen_US
dc.subject.pquncontrolledBCRen_US
dc.subject.pquncontrolledBtken_US
dc.subject.pquncontrolledSHIPen_US
dc.subject.pquncontrolledWASPen_US
dc.titleREGULATORY FUNCTIONS OF THE ACTIN CYTOSKELETON IN B CELL RECEPTOR SIGNALINGen_US
dc.typeDissertationen_US

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