Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Abstract

B cell Ag receptors function in both signaling activation of Ag-specific cells and in collecting specific Ag for presentation to T lymphocytes. Signaling via PI3K is required for BCR-mediated activation and Ag presentation functions; however, the relevant downstream targets of PI3K in B cells are incompletely defined. In this study, we have investigated the roles of the PI3K effector molecule Bam32/DAPP1 in BCR signaling and BCR-mediated Ag presentation functions. In mouse primary B cells, Bam32 was required for efficient activation of the GTPase Rac1 and downstream signaling to JNK, but not activation of BLNK, phospholipase C γ2, or calcium responses. Consistent with a role of this adaptor in Rac-mediated cytoskeletal rearrangement, Bam32 was required for BCR-induced cell adhesion and spreading responses on ICAM-1 or fibronectin-coated surfaces. The function of Bam32 in promoting Rac activation and adhesion required tyrosine 139, a known site of phosphorylation by Lyn kinase. After BCR crosslinking by Ag, Bam32-deficient B cells are able to carry out the initial steps of Ag endocytosis and processing, but show diminished ability to form Ag-specific conjugates with T cells and polarize F-actin at the B-T interface. As a result, Bam32-deficient B cells were unable to efficiently activate Ag-specific T cells. Together, these results indicate that Bam32 serves to integrate PI3K and Src kinase signaling to promote Rac-dependent B cell adhesive interactions important for Ag presentation function.

Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4+ Effector Memory T Cells

“…Additionally, there was a strongly suggestive association to rs3775500 on chromosome 4, located in the intron of DAPP1 , which encodes the Bam32 protein ( p  = 5.40×10 −7 ; Figure 4B ), which is an adaptor protein expressed solely in antigen presenting B cells. Interestingly, mutations in this gene have been shown by several groups to affect T cell activation [25], [26], suggesting the possibility that B cells may indirectly regulate T cell function in autoimmunity. We did not observe any significant association with the relative abundance of CD4 + T EM cells.…”

S1PR2 links germinal center confinement and growth regulation

“…DOCK8 is a member of the DOCK family, whose members contain a DOCK homology region 1 domain (DHR1), which recruits them to PIP3, and have Rho-Rac family GTP-exchange factor activity. Another PIP3-binding protein, Bam32, which is a pleckstrin homology domain adapter protein, was also found to be important for BCR-induced integrin adhesion and spreading as well as the formation of stable conjugates with T cells (107), and Bam32 deficiency resulted in a failure of GCs to persist after formation and a reduction in affinity maturation (108). Bam32-deficient GC B cells were more susceptible to apoptosis.…”

Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: A distinct branch of PI3K signaling

“…Together these results suggest that PI(3,4)P2 may have a role in migration via membrane recruitment of Akt or other binding proteins important for dynamic cytoskeletal reorganization.As discussed above the PI(3,4)P2-specific binding proteins TAPP2 and Lpd mediates chemokine-induced directional migration (chemotaxis) of malignant B cells[72] and random motility of several other cell types[97], respectively. Like Akt, a number of other signaling proteins can bind both PI(3,4)P2 and PIP3[4], such as SWAP-70[145,146], PDK1[120], PLCγ1[147], Bam32/DAPP1[56,148,149] and ARNO[56]. Recent data indicate involvements of these molecules in the migration of various cell types, as detailed below.…”