Genomic Structures and Chromosomal Location of p91, a Novel Murine Regulatory Receptor Family

Abstract

Recently, we found a novel murine cell-surface glycoprotein, designated as p91, expressed mainly in myeloid cells such as macrophages and mast cells. The molecule has six immunoglobulin-like extracellular domains, a transmembrane segment, and a cytoplasmic tail containing four immunoreceptor tyrosine-based inhibition motif (ITIM) or ITIM-like sequences, resembling the structural features of human killer-cell inhibitory receptors (KIR). Here we show that p91 comprises a polymorphic gene family, harboring one potent inhibitory-type p91 and at least two other p91 genes. Tyrosine-phosphorylated, but not nonphosphorylated, synthetic peptides matching the third ITIM and the fourth ITIM-like sequences, respectively, found in the cytoplasmic portion of p91A, the sole inhibitory-type p91, were associated with the tyrosine phosphatases, SHP-1 and SHP-2. In addition, the phosphotyrosyl peptide matching the third ITIM sequence also bound the inositol 5-phosphatase, SHIP. These results support the notion that p91A may function as an inhibitory cell-surface molecule against cell activation. The p91 genes were shown to be clustered in the proximal region of mouse chromosome 7, a syntenic position of human chromosome 19 where the genes for the KIR family are found. A human cDNA clone cross-hybridizing to a murine p91 probe was isolated from a human spleen cDNA library, and was found to code for a molecule quite similar to members of the immunoglobulin-like transcript (or ILT) family. The gene was found to be located on human chromosome 19q13.3-13.4. These results establish the existence of a novel set of potent regulatory receptors in mouse and man, similar but different from the KIR family.

Inhibition of IgE-mediated mast cell activation by the paired Ig-like receptor PIR-B

“…Although the SHP-1 protein tyrosine phosphatase is normally associated with PIR-B molecules, surprisingly, this phosphatase appears to be entirely dispensable in the PIR-B-mediated inhibition of IgE antibody-mediated mast cell activation. A third functional PIR-B ITIM identified in this study, the Y742-based ETYAQV motif, that failed to bind either protein tyrosine phosphatases (SHP-1 and SHP-2) or inositol polyphosphate 5-phosphatase (SHIP) (8,10,13), was found to associate with another potential regulatory element, a presently unidentified protein of approximately 120 kDa.…”

“…This charged amino acid could alter the properties of this motif relative to those of the consensus ITIM motif. The molecular mechanism through which which the Y742-based ITIM exerts its inhibitory function will be interesting to determine, especially in view of its inability to bind SHP-1, SHP-2, and SHIP (8,10,13). Instead, the PIR-B Y742 phosphopeptide was found to bind a protein of approximately 120 kDa, the identity of which remains to be elucidated.…”

A novel family of Ig-like receptors for HLA class I molecules that modulate function of lymphoid and myeloid cells

“…Another subset of receptors (ILT1, ILT1-like protein, ILT7, ILI8, and LIR6) contains short cytoplasmic domains that lack kinase homology or recognizable docking motifs for signaling mediators. In addition, they are characterized by the presence of a single basic arginine residue within the hydrophobic transmembrane domain [13,20,21]. These ILT receptors activate cells by associating with the gamma chain of Fc receptors (Fc␥R) that transduces stimulatory signals [22].…”

“…Further genomic studies are necessary to establish whether all of the cloned ILT5 variants are encoded by different alleles at the same locus or by different loci. Human ILT receptors are homologous to murine paired Ig-like receptors (PIRs) [21,27,28] and murine gp49 receptors [29][30][31][32][33]. PIRs are members of the Ig-superfamily characterized by six extracellular Ig-SF domains and by differing transmembrane and cytoplasmic domains.…”

Stimulatory Function of gp49A, a Murine Ig-Like Receptor, in Rat Basophilic Leukemia Cells

“…Many, but not all, inhibitory-type and noninhibitorytype Ig-like receptors within a subfamily tend to be expressed on cell surfaces in a pairwise fashion. For example, stimulating-type PIR-A and inhibitory PIR-B are coexpressed on many cell types (18,28,63). Like other Ig-like receptors, gp49A and gp49B are also coexpressed on mast cells and other cells, as shown at least in RT-PCR analysis (K. H. Lee and T. Takai, unpublished observation).…”