| The regulation of signaling and migration is critical to B lymphocyte development, activation, and proliferation. This dissertation reports a functional role for Fc receptor-like molecule 5 (FCRL5), a B cell specific member of the Fc receptor-like family of molecules, and the discovery of a novel family of conserved transmembrane proteins with fibronectin, immunoglobulin, and leucine-rich repeat domains (FIGLER) expressed in bone marrow and B lineage cells. Until now, the signaling potential of FCRL5 was unknown. A panel of FcgammaRIIB/FCRL5 chimeric receptors were created and expressed in a B cell line lacking endogenous FcgammaRIIB. Coligation of the chimeric receptor with the B cell antigen receptor (BCR) resulted in the marked inhibition of whole cell tyrosine phosphorylation, calcium mobilization, Erk activation, and Igalpha/Igbeta heterodimer phosphorylation. The inhibitory effect was shown to be mediated by dual ITIM recruitment of SHP-1, a SH2-containing protein tyrosine phosphatase. Although all 3 intracellular FCRL5 tyrosines are capable of being phosphorylated, only the ITIM tyrosines appear to contribute to the signaling potential of FCRL5 in the context of BCR signaling. Furthermore, the inhibitory effect of FCRL5 on BCR signaling was demonstrated in primary tonsillar memory B cells. The evidence presented represents the first evidence of the potent inhibitory potential of FCRL5 and the first signaling potential analysis of an Fc receptor-like family member containing both ITAM-like and ITIM signaling motifs. Secondly, using bioinformatic searches for molecules resembling the IL-7alpha receptor, a novel family of 9 human FIGLER genes was identified. The FIGLER family proteins encode type I transmembrane glycoproteins, with 612 leucine-rich repeats (LRRs), a single C2 Ig and FNIII domain, and cytoplasmic domain containing at least one tyrosine. In addition to the nine human FIGLER molecules, homologs were identified in macaque, orangutan, chimpanzee, mouse, rat, dog, chicken, toad, and puffer fish databases. FIGLER 1, 2, 3, and 5 mRNA transcripts were detected in primary B cell lines. The structure and lack of evident intracellular signaling motif indicate the FIGLER molecules may serve as trophic or cellular adhesion molecules. |
