based activation motif (ITAM)-like sequence and two consensus immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic region. To evaluate its signaling potential, we expressed constructs for chimeric molecules composed of the cytoplasmic region of FCRL5 and the extracellular and transmembrane regions of the IgG Fc receptor Fc{gamma}RIIB in a B cell line lacking an endogenous Fc receptor. Coligation of this fusion protein with the B cell receptor (BCR) inhibited BCR-mediated calcium mobilization, intracellular tyrosine phosphorylation, and Erk kinase activation. Our mutational analysis indicated that, whereas tyrosines in both the inhibitory and activation motifs are phosphorylated after ligation, only those in ITIMs influence BCR-mediated signaling. This FCRL5 inhibitory effect was mediated through dual ITIM recruitment of the SH2-containing protein tyrosine phosphatase, SHP-1, which in turn dephosphorylates the ITAM-based tyrosines in BCR Ig{alpha}/Igbeta heterodimers. An FCRL5 inhibitory effect on BCR signaling was likewise demonstrable for primary B cells. Although its ligand is presently unknown, we conclude that FCRL5 has the functional potential to serve as an inhibitory coreceptor on mature B cells in humans.

B cell receptor | Fc receptor-like protein 5 | inhibitory | SH2 domain-containing tyrosine phosphatase 1

B cell receptor (BCR) engagement initiates signaling cascades that lead to activation of the Ras-MAPK pathway, phosphatidylinositol-3-kinase, and phospholipase C {gamma} (PLC{gamma}) (1, 2). The BCR triggering ultimately induces gene expression patterns that can promote cell activation, apoptosis, or anergy, depending upon the balance of enhancing and inhibitory influences that vary according to the stage in B cell differentiation (3). Costimulatory or inhibitory coreceptors on B cells modulate BCR signaling to either enhance or attenuate downstream signaling cascades (4). Inhibitory coreceptors may dampen BCR signaling via an immunoreceptor tyrosine-based inhibition motif (ITIM) in their cytoplasmic region. When tyrosine phosphorylated, the ITIMs recruit protein tyrosine phosphatases and lipid phosphatases via Src homology 2 (SH2) domain binding to achieve down-regulation or neutralization of BCR-induced activation (5). Conversely, the costimulatory receptors may have their own cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAM) or they may pair with a transmembrane protein containing one or more ITAMs, whose tyrosines are phosphorylated by src family kinases to allow the recruitment of signaling molecules that promote cellular activation (6). The balance between activating and inhibitory receptor influences can be complicated by their coexpression on individual B cells. Moreover, individual cell surface receptors may possess both activating and inhibitory motifs; their differential engagement, according to ligand specificity and affinity, may trigger inhibitory and/or ac... [ Read More (0.3k in body) ]