UBC Theses and Dissertations
The role of the Rap GTPases in B-cell morphology, function, and malignancy Lin, Bin Liang Kevin
B-lymphocytes rearrange their cytoskeleton and undergo dramatic morphological changes when searching for antigens and when forming immune synapses upon contacting cells that display antigens on their surface. Although these morphological changes are essential to B cell function, the signaling pathways underlying these processes are not fully understood. The aim of this thesis is to investigate how B cell receptor (BCR) and integrin signaling regulate B cell morphological changes. The Rap GTPases (Rap) are molecular switches that regulate integrin activation, adhesion, migration in B cells and other cell types. I hypothesize that activation of the Rap GTPases is important for regulating changes in B cell morphology. Indeed, in this thesis I showed that activation of Rap is essential for B cell cytoskeletal rearrangements. I found that Rap activation is important for BCR- and lymphocyte function-associated antigen-1 (LFA-1)-induced spreading, for BCR-induced immune synapse formation, and for particulate BCR ligands to induce localized F-actin assembly and membrane process extension. Rap activation and F-actin assembly were also required for optimal BCR signaling in response to particulate antigens leading to B cell activation. Consistent with Rap activation being important for B cell adhesion and migration, I showed that Rap activation is important for the dissemination of B cell lymphomas in vivo. B cell lymphomas are common malignancies in which transformed B cells enter the circulation, extravasate into tissues, and form tumors in multiple organs. Lymphoma cells are thought to exit the vasculature and enter tissues via the same chemokine- and adhesion molecule-dependent mechanisms as normal B cells. Using A20 murine B lymphoma cells, I showed that Rap activation is important for circulating lymphoma cells to invade tissue and form tumors in vivo in syngeneic mice. Moreover, using in vitro models I showed that Rap activation is required for these cells to extend membrane processes between vascular endothelial cells and undergo transendothelial migration. Thus, by controlling B cell morphology and cytoskeletal organization, the Rap GTPases play a key role in both malignant and normal B cell functions, and may be a potential therapeutic target for treatment of B cell-related diseases.
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