| dc.description.abstracteng | Stimulation of the B cell antigen receptor (BCR) triggers an intracellular signaling cascade through its integral signaling components Igα and Igβ. This signaling cascade involves several protein classes like kinases, lipases and adaptor molecules and ultimately leads to nuclear translocation of transcription factors such as NF-κB and NFAT, promotes proliferation and metabolism via the PI3K/Akt kinase pathway, induces actin remodeling and activates MAPK like JNK, Erk and p38. The signaling cascade downstream of the BCR plays a crucial role in the life of B cells, starting from maturation of the cells in the bone marrow to activation and differentiation in peripheral lymphoid organs. Any dysregulation of this pathway can cause severe diseases such as immunodeficiencies, autoimmune diseases or malignancies. Hence,
it is important to understand the biochemical mechanisms by which this signaling pathway is controlled. However, the exact function of some of the involved players, such as the Vav family of guanine nucleotide exchange factors, still remains only partially understood. Using a cellular model system based on a Vav1-deficient subline of a human B cell line, our group revealed a critical role of Vav family members for BCR-proximal signaling reactions including mobilization of the second messenger Ca2+. This work unraveled several other signaling axes within the BCR signaling cascade, such as induction of actin remodeling, activation of MAPK p38 and
Erk and phosphorylation of Akt, that depend on the expression of Vav family members. Strikingly, all of those signaling axes were significantly impeded upon loss of the catalytic guanine-nucleotide exchange factor (GEF) activity of Vav family members. Interestingly, Vav2 was able to mediate BCR-induced actin remodeling and phosphorylation of Akt even though it does not support BCR-induced Ca2+-mobilization. In vitro GEF-activity assays revealed Vav family isoform-specific activation of the Rho family. Whereas Vav1 mediated activation of Rac1
and RhoA, Vav2 selectively activated Rac1 and Vav3 showed GEF activity only towards RhoA. Thus, activation of RhoA appears to be required for BCR-induced Ca2+-mobilization while GEFactivity towards Rac1 supports actin remodeling and phosphorylation of Akt upon stimulation of the BCR. Consequently, a new class of catalytic activity, i.e. the GEF-activity of Vav family proteins towards different Rho family small G proteins, was identified to be required for BCR-induced signaling. Moreover, it was shown, that the BCR-induced activation of Akt, actin cytoskeleton remodeling and Ca2+-influx were independent from each other. This work
suggests that Vav family members do not just act as adaptor proteins in the BCR signaling cascade but represent central enzymatic coordinators of distinct signaling pathways
downstream of the BCR. | de |