LAIR-1, a Novel Inhibitory Receptor Expressed on Human Mononuclear Leukocytes

Meyaard, Linde; Adema, Gosse J.; Chang, Chiwen; Woollatt, Erica; Sutherland, Grant R.; Lanier, Lewis L.; Phillips, Joseph H.

doi:10.1016/s1074-7613(00)80530-0

Cited by 359 publications

(359 citation statements)

References 43 publications

Supporting

Mentioning

349

Contrasting

Order By: Relevance

“…Human myeloid cells express several other inhibitory receptors such as CD31/PECAM-1 (31), Fc␥RIIb (32), LAIR-1 (33), and several members of immunoglobin-like transcript receptor family (34). Ligation of these receptors has been shown to modulate a range of leukocyte functions, including migration, proliferation, apoptosis, and cellular activation.…”

Section: Discussionmentioning

confidence: 99%

Siglec-5 (CD170) Can Mediate Inhibitory Signaling in the Absence of Immunoreceptor Tyrosine-based Inhibitory Motif Phosphorylation

Avril

Freeman

Attrill

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Siglec-5 (CD170) is a member of the recently described human CD33-related siglec subgroup of sialic acid binding Ig-like lectins and is expressed on myeloid cells of the hemopoietic system. Similar to other CD33-related siglecs, Siglec-5 contains two tyrosine-based motifs in its cytoplasmic tail implicated in signaling functions. To investigate the role of these motifs in Siglec-5-dependent signaling, we used transfected rat basophil leukemia cells as a model system. Tyrosine phosphorylation of Siglec-5 led to recruitment of the tyrosine phosphatases SHP-1 and SHP-2, as seen in both pull-down assays and microscopy. Siglec-5 could efficiently inhibit Fc⑀RI-mediated calcium fluxing and serotonin release after cocross-linking. Surprisingly, a double tyrosine to alanine mutant of Siglec-5 could still mediate strong inhibition of serotonin release in the absence of detectable tyrosine phosphorylation, whereas a double tyrosine to phenylalanine mutant lost all inhibitory activity. In comparison, suppression of Siglec-5-dependent adhesion to red blood cells was reversed by either tyrosine to alanine or tyrosine to phenylalanine mutations of the membrane proximal tyrosine-based motif. Using an in vitro phosphatase assay with synthetic and recombinant forms of the cytoplasmic tail, it was shown that a double alanine mutant of Siglec-5 had weak, but significant SHP-1 activating properties similar to those of wild type, non-phosphorylated cytoplasmic tail, whereas a double phenylalanine mutant was inactive. These findings establish that Siglec-5 can be classified as an inhibitory receptor with the potential to mediate SHP-1 and/or SHP-2-dependent signaling in the absence of tyrosine phosphorylation.Regulation of responses by cells in the hemopoietic and immune systems depends on a balance between activatory signaling and inhibitory signaling. Their relative strengths set an appropriate activation threshold that helps fine-tune the response. Inhibitory signals are typically initiated by receptors containing one or more cytoplasmic immunoreceptor tyrosinebased inhibitory motifs (ITIMs) 1 (1). The consensus sequence for ITIMs is (V/I/L)XYXX(L/V), where X is any amino acid. A recent bioinformatics study showed that the human proteome contains ϳ109 membrane proteins with cytoplasmic ITIMs, and many of these have been shown already to function as inhibitory receptors (2). The established dogma is that Src family tyrosine kinases phosphorylate the tyrosine residue in ITIMs during cellular activation and create high affinity docking sites for SH2 domain-containing phosphatases such as protein-tyrosine phosphatases SHP-1 and SHP-2 and the 5Ј inositol phosphatase, SHIP (1). The recruited and activated phosphatases can then dephosphorylate relevant substrates in the vicinity and regulate cellular activation (3). The human CD33-related siglecs are a recently described subgroup of the siglec family of sialic acid binding immunoglobulin (Ig)-like lectins (4). All eight human CD33-related siglecs are expressed by cells of the hemopoietic...

show abstract

Section: Discussionmentioning

confidence: 99%

Siglec-5 (CD170) Can Mediate Inhibitory Signaling in the Absence of Immunoreceptor Tyrosine-based Inhibitory Motif Phosphorylation

Avril

Freeman

Attrill

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Genes encoding ILT receptors map on human chromosome 19q13.4, in close linkage with the KIR genes, the Fc␣R gene and the gene encoding the recently discovered inhibitory receptor LAIR [23][24][25][26]. Sequence analysis of the KIR-ILT region, contained in contiguous bacterial artificial chromosomes (BACs), has revealed the existence of at least eight distinct ILT loci and two pseudo genes.…”

Section: Ilt Receptor Structurementioning

confidence: 99%

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

Colonna

Nakajima

Navarro

et al. 1999

Journal of Leukocyte Biology

155

109

View full text Add to dashboard Cite

“…3B). The ITIM was initially defined in FC␥RB (34) and later in many other hematopoietic cell proteins, including KIR (35) and LAIR (36). Interestingly, this motif is also found in SIRP/SHPS-1, a putative SHP-2 substrate that has recently been cloned (23,24).…”

Section: Identification and Purification Of A 43-kda Hyperphosphorylamentioning

confidence: 99%

Purification and Cloning of PZR, a Binding Protein and Putative Physiological Substrate of Tyrosine Phosphatase SHP-2

Zhao

1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

Overexpression of a catalytically inactive mutant of tyrosine phosphatase SHP-2 in 293 cells resulted in hyperphosphorylation of a glycoprotein specifically associated with the enzyme. The protein has been purified to near homogeneity. Based on the amino acid sequences of peptides obtained from the protein, a full-length cDNA was isolated. The cDNA encodes a protein with a single transmembrane segment and a signal sequence. The extracellular portion of the protein contains a single immunoglobulin-like domain displaying 46% sequence identity to that of myelin P0, a major structural protein of peripheral myelin. The intracellular segment of the protein shows no significant sequence identity to any known protein except for two immunoreceptor tyrosine-based inhibitory motifs. We name the protein PZR for protein zero related. Transfection of the PZR cDNA in Jurkat cells gave rise to a protein of expected molecular size. Stimulation of cells with pervanadate resulted in tyrosine phosphorylation of PZR and a nearstoichiometric association of PZR with SHP-2. Northern blotting analyses revealed that PZR is widely expressed in human tissues and is particularly abundant in heart, placenta, kidney, and pancreas. As a binding protein and a putative substrate of SHP-2, PZR protein may have an important role in cell signaling.Protein tyrosine phosphatases (PTPs) 1 represent a highly diverse family of enzymes that have a pivotal role in cell proliferation, differentiation, and transformation (1-3). SHP-1 and SHP-2, representing a subfamily of PTPs containing Src homology 2 domains have been extensively studied in recent years (for review, see Refs. 4 -11). These two enzymes share nearly 60% overall sequence identity and are regulated in similar manners. Nevertheless, in many systems, they have distinct physiological functions. SHP-1 has a negative role in proliferation of hematopoietic cells, whereas SHP-2 is a positive transducer of growth factor signal transduction. This distinction in functions is presumably attributable to different physiological targets. Recently, a number putative substrates of SHP-1 and SHP-2 have been identified (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and one of them, designated SIRP or SHPS-1, has been cloned (23, 24). In our earlier studies, by overexpressing catalytically inactive mutants of SHP-1 and SHP-2, we have identified several hyperphosphorylated proteins associated with the inactive SHP-1 and/or SHP-2 (25, 26). Among these is a 43-kDa membrane protein that is specifically associated with SHP-2. Here we report the purification and molecular cloning of this protein. It represents a novel transmembrane protein with an extracellular segment homologous to myelin protein zero and an intracellular portion containing two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). We name it PZR for protein zero related. EXPERIMENTAL PROCEDURESMaterials-Polyclonal anti-SHP-1 and anti-SHP-2 antibodies were raised in rabbits against full-length SHP-1 and an Src homology 2 domain-truncated form of SH...

show abstract

LAIR-1, a Novel Inhibitory Receptor Expressed on Human Mononuclear Leukocytes

Cited by 359 publications

References 43 publications

Siglec-5 (CD170) Can Mediate Inhibitory Signaling in the Absence of Immunoreceptor Tyrosine-based Inhibitory Motif Phosphorylation

Siglec-5 (CD170) Can Mediate Inhibitory Signaling in the Absence of Immunoreceptor Tyrosine-based Inhibitory Motif Phosphorylation

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

Purification and Cloning of PZR, a Binding Protein and Putative Physiological Substrate of Tyrosine Phosphatase SHP-2

Contact Info

Product

Resources

About