SYK regulates B-cell migration by phosphorylation of the F-actin interacting protein SWAP-70

Abstract

IntroductionMigration of B cells into secondary lymphoid organs is required for an antigen-specific humoral immune response. B cells migrate from the bloodstream to lymph nodes by extravasation from high endothelial venules. The response to chemokines and integrinmediated adhesion to endothelial cells is a key step in this process. 1 B cells in secondary lymphoid organs are critical to homeostatic and inflammatory regulation of these tissues. If the lymph node becomes inflamed, B-cell migration is a prerequisite for normal hypertrophy and the further recruitment of dendritic and T cells. 2 B-cell trafficking within lymph nodes is also important during the generation of the germinal center reaction and humoral immune responses. [3][4][5][6] Abnormal chemoattractant-mediated B-cell migration is central to infiltration of malignant B cells into tissues and formation of ectopic germinal centers in autoimmune diseases. [7][8][9] The transduction of signals from cell surface receptors to the actin cytoskeleton to regulate cell adhesion and migration requires small G proteins of the Ras superfamily. [10][11][12] These include members of the Ras family, including Ras and Rap1, and members of the Rho family, such as Rac, Cdc42, and Rho. 13 Upstream activators of Rho proteins such as the Dbl homology domain proteins of the Vav family are required for ␤-integrin and chemokine-mediated Rac, Cdc42, and Rho activation and stable adhesions of cells. 14 Although B-cell migration is vital for their development, the pathways underlying integrin and chemokine signals in B cells are poorly defined. We identified the signaling protein SWAP-70 15 as required for B-cell migration and adhesion in vitro and in vivo. 16 Swap70 Ϫ/Ϫ B cells show aberrant integrin-mediated adhesion, defective polarization, and do not form uropods and stabilized lamellipodia in vitro. This leads to a defect in migration and homing of B cells to lymph nodes in vivo. In correlation with these defects in migration and adhesion, Swap70 Ϫ/Ϫ transitional B cells hyperadhere to the splenic red pulp and are impaired in differentiation into marginal zone B-cells. 17 In addition, Swap70 Ϫ/Ϫ B cells do not generate a normal germinal center response, 18 a process requiring high B-cell motility and a dynamic morphology, 6 which are most likely disturbed by the absence of SWAP-70.SWAP-70 interacts with and regulates proteins of the Rho family, in particular Rac and RhoA. 19,20 Unusually, SWAP-70 has a Dbl homology domain to the C-terminus of its pleckstrin homology (PH) domain. 20 The PH domain binds PIP 3 and SWAP-70 also binds F-but not G-actin. 20,21 The binding of SWAP-70 to F-actin depends on cell stimulation and is required for regulation of cytoskeletal rearrangements such as membrane ruffles. 21 Although its regulation of Rac and actin polymerization are likely to be important for SWAP-70's function in regulating B-cell migration, little is known about how SWAP-70 itself is regulated, other than its interaction with PIP 3 , which is required for its localization. ...

IL-21 Enhances the Activity of the TLR–MyD88–STAT3 Pathway but Not the Classical TLR–MyD88–NF-κB Pathway in Human B Cells To Boost Antibody Production

“…Indeed, a Syk inhibitor abrogated the effect of IL-21 on TLR-induced IgG production but not IL-6 production (7). Although we cannot exclude the possible off-target effect of the Syk inhibitors used in our assay, we consider it most likely that our results are explained by syk inhibition, which is in line with previous studies where the same inhibitors were used (32)(33)(34). Our data indicate that IL-21 enhances IgG production through modulating the TLR-MyD88-Syk-STAT3 pathway but not the TLR-MyD88-NF-kB pathway, which is further confirmed by our finding that stimulation of B cells with IL-21 and TLR agonists resulted in an increased activation of STAT3.…”

TLR4 Signaling Shapes B Cell Dynamics via MyD88-Dependent Pathways and Rac GTPases

“…In addition, TLR9 signaling leads to Syk activation via the MyD88 pathway in B cells (31). Syk is involved in integrin activation and cell migration downstream of chemokine receptors and the BCR (32,33). Further studies are needed to address the roles of PI3K and Syk in the modulation of B cell dynamics by TLR signaling.…”

Vinculin Arrests Motile B Cells by Stabilizing Integrin Clustering at the Immune Synapse

“…Syk is important for integrin activation by the BCR (32) and by chemokine receptor stimulation (33). We compared the intensity of signals transmitted through the BCR after tAg and sAg stimulation by measuring p-Syk levels in B cells.…”