PILRα, a Novel Immunoreceptor Tyrosine-based Inhibitory Motif-bearing Protein, Recruits SHP-1 upon Tyrosine Phosphorylation and Is Paired with the Truncated Counterpart PILRβ

Abstract

SHP-1-mediated dephosphorylation of protein tyrosine residues is central to the regulation of several cell signaling pathways, the specificity of which is dictated by the intrinsic affinity of SH2 domains for the flanking sequences of phosphotyrosine residues. By using a modified yeast two-hybrid system and SHP-1 as bait, we have cloned a human cDNA, PILR␣, encoding a 303-amino acid immunoglobulin-like transmembrane receptor bearing two cytoplasmic tyrosines positioned within an immunoreceptor tyrosine-based inhibitory motif. Substrate trapping in combination with pervanadate treatment of 293T cells confirms that PILR␣ associates with SHP-1 in vivo upon tyrosine phosphorylation. Mutation of the tyrosine residues in PILR␣ indicates the pivotal role of the Tyr-269 residue in recruiting SHP-1. Surface plasmon resonance analysis further suggests that the association between PILR␣-Tyr-269 and SHP-1 is mediated primarily via the amino-terminal SH2 domain of the latter. Polymerase chain reaction amplification of cDNA in combination with genomic sequence analysis revealed a second gene, PILR␤, coding for a putative activating receptor as suggested by a truncated cytoplasmic tail and a charged lysine residue in its transmembrane region. The PILR␣ and PILR␤ genes are localized to chromosome 7 which is in contrast with the mapping of known members of the inhibitory receptor superfamily.

IREM‐1 is a novel inhibitory receptor expressed by myeloid cells

“…A putative IREM-1 murine orthologue, CLM-1, has been recently shown to be also expressed mainly by myeloid cells [19]. A myeloidrestricted expression pattern has been observed for a number of immunoreceptors, such as TREM-1 [4] and PILRa [20], some ILT [21,22], and IREM-2, another member of the same family (Aguilar et al, submitted), indicating a possible role for these molecules in the regulation of the innate immune response. IREM-1 and IREM-2 are the only known members of the CMRF-35 family with a myeloid-restricted expression pattern; it is of note that UP-D1 and UP-D2 mAb do not cross-react with IREM-2.…”

Identification of paired immunoglobulin-like type 2 receptor α as hepatitis B virus DNA polymerase transactivated protein 1 interacting proteins

“…As PILRA binds with its ligand (primary cytokines), it is triggered to form homodimers and cause self-phosphorylation and activation of the non-receptor tyrosine kinase, Janus-activated kinase (JAK), which is followed by catalyzing the phosphorylation of tyrosine residues in ITIMs. At the same time, potential docking sites containing two Src homology 2 (SH2) domains of SH2-containing phosphatase 1 (SHP-1) tyrosine phosphatase are formed (16,17). Once SHP-1 is docked at this docking site, the dephosphorylation of JAK and its downstream signaling molecules, signal transducers and activators of transcription (STAT), can be catalyzed, and thereby terminate the cell proliferation signal or induce an apoptosis signal (18,19).…”

Evolutionarily Conserved Paired Immunoglobulin-like Receptor α (PILRα) Domain Mediates Its Interaction with Diverse Sialylated Ligands

“…Likewise, the PILR␣ extracellular domain (ECD) shares two evolutionarily conserved arginines with SIGLECs, one of which is located in a ␤-strand potentially involved in ligand interactions. In this context, it is important to note that the Ig-like domain of PILR␣ has only 30% homology to other Ig superfamily domains, so it is possible that unique interacting domains might have evolved within PILR␣ (4,5,7,22). Although seemingly distinct gene families, the conservation of certain residues between PILR␣ and SIGLECs begs the question whether these residues are involved in PILR␣/ligand recognition.…”

“…Human paired immunoglobulin-like receptors (PILR) 2 ␣ and ␤ are related type I transmembrane receptors. PILR␣ and -␤ share high similarity in their extracellular domain but contain highly divergent intracellular signaling domains and resulting functions (4,5). PILR␣ is predominantly expressed in cells of the myelomonocytic lineage, including monocytes/macrophages, granulocytes, and dendritic cells (4,6).…”

“…PILR␣ is predominantly expressed in cells of the myelomonocytic lineage, including monocytes/macrophages, granulocytes, and dendritic cells (4,6). PILR␣ has two cytoplasmic immunoreceptor tyrosine-based inhibitory motifs that recruit SHP-1 and SHP-2 to trigger an inhibitory signaling cascade such as reduced intracellular calcium mobilization (4,5). PILR␤, however, associates with the immunoreceptor tyrosinebased activation motif-bearing DAP12 adaptor molecule to deliver activating signals (6).…”