Dissertation/Thesis Abstract

Regulatory functions of the actin cytoskeleton in B cell receptor signaling
by Liu, Chaohong, Ph.D., University of Maryland, College Park, 2013, 221; 3599621
Abstract (Summary)

The 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.

Indexing (document details)
Advisor: Song, Wenxia
Commitee: Frauwirth, Kenneth, Upadhyaya, Arpita, Xiao, Zhengguo, Zhu, Xiaoping
School: University of Maryland, College Park
Department: Cell Biology and Molecular Genetics
School Location: United States -- Maryland
Source: DAI-B 75/02(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Immunology
Keywords: Actin cytoskeleton, B cell receptor, Bruton’s tyrosine kinase, Wiskott-Aldrich syndrome protein
Publication Number: 3599621
ISBN: 9781303491283