The role of Vav family guanine nucleotide exchange factors and their substrates in B cell antigen receptor signaling
Final Report Abstract
The B cell antigen receptor (BCR) is involved in almost every aspect of B cell biology and controls antigen‐independent aspects such as development and survival of the cells as well as their antigen‐ triggered activation and differentiation into plasma cells. While the basic principles of signal initiation and propagation that are employed by the BCR have been investigated in considerable detail over the last decades, a few central aspects remain incompletely understood. Two of those key aspects are i) the exact function of Vav family proteins in the BCR signaling cascade and ii) the nano‐scale organization of BCR complexes in the plasma membrane. Using a combination of genetic and biochemical approaches, we could demonstrate that the catalytic guanine nucleotide exchange factor (GEF) activity of distinct members of the Vav protein family is essential for proper BCR signal initiation and propagation in a human B cell model system. These findings are in contrast to previous results obtained from T lymphocytes, in which the GEF activity of Vav proteins appears to be less important if not obsolete to initiate TCR signaling. By using state of the art super‐resolution imaging techniques, we could furthermore show that the IgM‐BCR of native, primary human B cells is predominantly arranged in monomeric form in the plasma membrane, while there are only few small oligomers. Altogether, these results extend our understanding of the BCR and its associated signaling machinery as they reveal that the latter is not only controlled by kinases, phosphatases and lipid‐modifying enzymes as previously thought, but also by an additional class of enzymatic activity that is provided by GEFs of the Vav family. This knowledge may be used to develop novel pharmacological strategies to treat B cell‐related diseases that depend on chronic or aberrant BCR signaling.
Publications
- 2019. Differential organization of tonic and chronic B cell antigen receptors in the plasma membrane. Nature Communications
Gomes de Castro, M.A., Wildhagen, H., Sograte‐Idressi S., Hitzing, C., Binder, M., Trepel, M., Engels, N. & Opazo, F.
(See online at https://doi.org/10.1038/s41467-019-08677-1) - Vav family proteins constitute disparate branching points for distinct BCR signaling pathways. European journal of immunology
Löber, J., Hitzing, C., Münchhalfen, M. & Engels, N.
(See online at https://doi.org/10.1002/eji.202048621)
