| Summary: | The ability of the B cell receptor (BCR) to stimulate integrin-mediated adhesion, and induce cytoskeletal reorganization and cell spreading enhances the ability of B cells to bind and respond to antigens (Ag). The proper localization and trafficking of B cells in the secondary lymphoid organs are also critical for B cells to encounter Ags and to be activated. Proline-rich tyrosine kinase (Pyk2) and focal adhesion kinase (FAK) are related cytoplasmic tyrosine kinases that have been shown to regulate cell adhesion, morphology, and migration. However, their functions in B cells are not clear. The overall hypothesis of this thesis was that Pyk2 and FAK are downstream targets of BCR, integrin, and chemokine receptor signaling, and that they are involved in B cell morphological regulation, migration, and adhesion. I showed that the BCR and integrins collaborate to induce the phosphorylation of Pyk2 and FAK on key tyrosine residues, modifications that increase the kinase activity of Pyk2 and FAK. Activation of the Rap1 GTPase is critical for BCR-induced integrin activation and for BCR-induced reorganization of the actin cytoskeleton and I showed that inhibition of Pyk2 and FAK function by either gene knockdown or the use of chemical inhibitors impaired B cell spreading.
Marginal zone (MZ) B cells are innate-like B cells that are responsible for T cell-independent responses to microbial pathogens. The proper localization of MZ B cells is dependent on integrated migration and retention signals provided by the stromal cells in the spleen. Because MZ B cells are not found in Pyk2-/- mice, I hypothesized that Pyk2 and FAK are involved in MZ B cell retention in the spleen. I showed that Pyk2 and FAK are required for MZ B cell migration and that Pyk2 is required for integrin-dependent adhesion in response to chemoattractant stimulation. Moreover, I found that FAK is involved in chemokine-induced Akt phosphorylation in MZ B cells.
In summary, Pyk2 and FAK are downstream targets of the Rap GTPases and play a key role in regulating B cell morphology, migration, and adhesion.
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