Fc receptor-like protein 3 is a protein that in humans is encoded by the FCRL3 gene. This gene encodes a member of the immunoglobulin receptor superfamily and is one of several Fc receptor-like glycoproteins clustered on the long arm of chromosome 1. The encoded protein contains immunoreceptor-tyrosine activation motif (ITAM) and immunoreceptor-tyrosine inhibitory motif (ITIM) in its cytoplasmic domain and may play a role in regulation of the immune system. Mutations in this gene have been associated with rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus erythematosus. Structure Fc receptor-like protein 3 is a type I transmembrane glycoprotein, which consists of an extracellular region, a transmembrane domain and a cytoplasmatic tail. The extracellular region consists of five immunoglobulin-like domains, which share varying degree of homology to extracellular domains of other Fc receptor-like protein family members, as well as extracellular domains of Fc receptors FcγRI, FcγRII and FcγRIII. The transmembrane region consists of hydrophobic residues and is uncharged. The cytoplasmatic region contains two signalling motifs, a membrane-proximal ITAM and a carboxy-proximal ITAM-like motif. The presence of both an activating and inhibitory motifs suggests potential dual-signalling properties. Signalling Fc receptor-like protein 3 has a role in regulation in both innate and adaptive signalling pathways in association with other signalling molecules. It contains both an activation (ITAM-like) and an inhibitory (ITIM) motif in its cytoplasmic region, pointing to its dual-regulatory potential. FCRL3 is capable of associating with intracellular signalling molecules including Syk, Zap-70, SHP-1, and SHP-2. Activation properties of FCRL3 were observed in relation to TLR9-mediated signalling. FCRL3 engagement with receptor-specific monoclonal antibodies (mAbs) augmented TLR9-mediated blood B cell survival, proliferation and activation. It led to improved expression of activation markers CD25, CD86 and HLA-DR on cell surface via CpG-mediated NFκB and MAPK pathways activation. Expression of CD54 and CD80 was not significantly altered by this ligation. CpG signalling could potentially enhance differentiation of B cells into Ig-secreting plasma cells. But, FCRL3 ligation with mAbs halted differentiation of antibody secreting plasma B cells by inhibiting B-lymphocyte-induced maturation protein 1 (BLIMP1) expression via Erk signalling pathway. Inhibitory role of FCRL3 has been described in its negative regulation of B-cell receptor (BCR) signalling. Co-ligation of FCRL3 with BCR facilitates SHP-1 and SHP-2 recruitment via its intracellular ITIM motif. This leads to inhibition of Syk kinase and PLCγ2 phopshorylation, which suppresses downstream calcium signalling and apoptosis. FCRL3 has no known ligands. Expression Fc receptor-like protein 3