Constitutive tyrosine phosphorylation of the inhibitory paired Ig-like receptor PIR-B

Ho, Le Hong; Uehara, Takahiro; Chen, Ching-Cheng; Kubagawa, Hiromi; Cooper, Max D.

doi:10.1073/pnas.96.26.15086

Cited by 98 publications

(81 citation statements)

References 41 publications

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“…PIR-B is constitutively phosphorylated in resting B cells, and stimulation of those cells by Ag does not further enhance its phosphorylation (42). In contrast, in resting, nonadherent primary macrophages, we find that PIR-B is negligibly phosphorylated, and its phosphorylation can be inducibly increased by integrin engagement (16).…”

Section: Discussionmentioning

confidence: 56%

“…It functions predominantly as a negative regulator in BCR, Fc⑀R, integrin, and cytokine signaling (16, 38 -41). PIR-B has been demonstrated to be a substrate of Lyn, because PIR-B phosphorylation is dramatically reduced in B cells and macrophages isolated from lyn Ϫ/Ϫ mice (16,42). There are striking similarities between the responses of pir-b Ϫ/Ϫ and lyn Ϫ/Ϫ PMNs and macrophages to integrin cross-linking.…”

Section: Discussionmentioning

confidence: 80%

“…In contrast, in macrophages, PIR-B may function as an inducible regulator. However, in both B cells and macrophages and possibly mast cells, it appears that Lyn is the kinase that regulates PIR-B phosphorylation (16,42).…”

Section: Discussionmentioning

confidence: 99%

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The Inhibitory Receptor PIR-B Negatively Regulates Neutrophil and Macrophage Integrin Signaling

Pereira

Zhang

Takai

et al. 2004

The Journal of Immunology

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The Ig-like receptor family member, PIR-B, has been shown to play an inhibitory role in receptor signaling within B cells, mast cells, and dendritic cells. As it has been implicated in integrin-mediated responses, we investigated the effect of loss of the PIR-B protein on integrin-mediated signaling in primary murine myeloid cells. The pir-b−/− neutrophils displayed enhanced respiratory burst, secondary granule release, and a hyperadhesive phenotype when plated on surfaces coated with either extracellular matrix proteins or cellular adhesion molecules in the presence or absence of the soluble inflammatory agonist TNF-α. The pir-b−/− and wild-type cells responded equivalently when stimulated with TNF-α in suspension, indicating that the hyperresponsive phenotype of the pir-b−/− cells during adhesion was due to enhanced integrin signaling. Both wild-type and pir-b−/− neutrophils expressed similar levels of integrin subunits. Primary bone marrow-derived macrophages from pir-b−/− mice were also hyperadhesive and spread more rapidly than wild-type cells following plating on surfaces that cross-linked cellular β2 integrins. Biochemical analysis of macrophages from pir-b−/− mice revealed enhanced phosphorylation and activation of proteins involved in integrin signaling. These observations point to a nonredundant role for PIR-B in the regulation of leukocyte integrin signaling.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 80%

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The Inhibitory Receptor PIR-B Negatively Regulates Neutrophil and Macrophage Integrin Signaling

Pereira

Zhang

Takai

et al. 2004

The Journal of Immunology

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“…The ligands for LIR are class I MHC molecules, and recognition of MHC class I by these inhibitory receptors on human dendritic cells has been implicated in regulating T cell activation and tolerance induction (42,43). Although the ligand for PIR-B is still unclear, some recent evidence suggests that PIR-B may also recognize MHC class I molecules (44). Furthermore, PIR-B Ϫ/Ϫ mice have recently been generated and found to have defective dendritic cell maturation and altered T cell responses (45).…”

Section: Discussionmentioning

confidence: 99%

CD8+ T Cells Accumulate in the Lungs of Mycobacterium tuberculosis-Infected Kb−/−Db−/− Mice, But Provide Minimal Protection

Urdahl

Liggitt²,

Bevan

2003

The Journal of Immunology

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Recent studies have shown that MHC class I molecules play an important role in the protective immune response to Mycobacterium tuberculosis infection. Here we showed that mice deficient in MHC class Ia, but possessing MHC class Ib (Kb−/−Db−/− mice), were more susceptible to aerosol infection with M. tuberculosis than control mice, but less susceptible than mice that lack both MHC class Ia and Ib (β2m−/− mice). The susceptibility of Kb−/−Db−/− mice cannot be explained by the failure of CD8+ T cells (presumably MHC class Ib-restricted) to respond to the infection. Although CD8+ T cells were a relatively small population in uninfected Kb−/−Db−/− mice, most already expressed an activated phenotype. During infection, a large percentage of these cells further changed their cell surface phenotype, accumulated in the lungs at the site of infection, and were capable of rapidly producing IFN-γ following TCR stimulation. Histopathologic analysis showed widespread inflammation in the lungs of Kb−/−Db−/− mice, with a paucity of lymphocytic aggregates within poorly organized areas of granulomatous inflammation. A similar pattern of granuloma formation has previously been observed in other types of MHC class I-deficient mice, but not CD8α−/− mice. Thus, neither the presence of MHC class Ib molecules themselves, nor the activity of a population of nonclassical CD8+ effector cells, fully restored the deficit caused by the absence of MHC class Ia molecules, suggesting a unique role for MHC class Ia molecules in protective immunity against M. tuberculosis.

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“…This did not account for all of the inhibition observed with Lyn, suggesting that additional mechanisms contribute to Lyn-mediated down-regulation of Btk pathways. These may include inhibition by the cell surface receptor PIR-B, a pathway shown to involve both Btk and Lyn (75,76 The reduced TNP-Ficoll responses in both CD19 Ϫ/Ϫ Btk lo and p85␣ ϩ/Ϫ Btk lo mice supports a model in which CD19 amplifies Btk activation via PI3K (61,62). p85␣ was more penetrant than CD19, however.…”

Section: Discussionmentioning

confidence: 83%

A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase

Satterthwaite

Willis

Kanchanastit

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Modifier screens have been powerful genetic tools to define signaling pathways in lower organisms. The identification of modifier loci in mice has begun to allow a similar dissection of mammalian signaling pathways. Transgenic mice (Btk lo ) expressing 25% of endogenous levels of Bruton's tyrosine kinase (Btk) have B cell functional responses between those of wild-type and Btk ؊/؊ mice. We asked whether reduced dosage or complete deficiency of genes previously implicated as Btk regulators would modify the Btk lo phenotype. We used two independent assays of Btk-dependent B cell function. Proliferative response to B cell antigen receptor cross-linking in vitro was chosen as an example of a relatively simple, well-defined signaling system. In vivo response to type II T-independent antigens (TI-II) measures complex interactions among multiple cell types over time and may identify additional Btk pathways. All modifiers identified differentially affected these two assays, indicating that Btk mediates these processes via distinct mechanisms. Loss of Lyn, PTEN (phosphatase and tensin homolog), or SH2-containing inositol phosphatase suppressed the Btk lo phenotype in vitro but not in vivo, whereas CD19 and the p85␣ form of phosphoinositide 3-kinase behaved as Btk lo enhancers in vivo but not in vitro. Effects of Lyn, PTEN, or p85␣ haploinsufficiency were observed. Haploinsufficiency or complete deficiency of protein kinase C ␤, Fyn, CD22, G␣q, or G␣11 had no detectable effect on the function of Btk lo B cells. A transgenic system creating a reduction in dosage of Btk can therefore be used to identify modifier loci that affect B cell responses and quantitatively rank their contribution to Btk-mediated processes.In vivo genetic analysis is a powerful approach to define the relative contribution of signaling interactions to physiological processes. Small genomes, ease of mutagenesis, and rapid generation time have made Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae the major models for genetic dissection of eukaryotic signaling pathways. Although there are some examples of large-scale genetic screens in mice (1-3), time, space, and financial resources generally limit mammalian genetic studies to targeted mutations in known genes or the characterization of naturally occurring mutations.In a commonly used type of genetic screen, organisms carrying a defined mutation affecting the process of interest are further mutagenized and screened for second site mutations, or modifiers, that enhance (increase) or suppress (reduce) the severity of the parental phenotype (4, 5). The initial mutation often renders the system responsive to subtle changes in modifiers that would not be penetrant on an otherwise wild-type background. This sensitivity often permits a dominant screen, decreasing the time and resources required to identify new mutations.Complete deficiency of many signaling molecules results in loss of the cell type of interest or pleiotropic or lethal phenotypes, making the effects of additional m...

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Constitutive tyrosine phosphorylation of the inhibitory paired Ig-like receptor PIR-B

Cited by 98 publications

References 41 publications

The Inhibitory Receptor PIR-B Negatively Regulates Neutrophil and Macrophage Integrin Signaling

The Inhibitory Receptor PIR-B Negatively Regulates Neutrophil and Macrophage Integrin Signaling

CD8+ T Cells Accumulate in the Lungs of Mycobacterium tuberculosis-Infected Kb−/−Db−/− Mice, But Provide Minimal Protection

A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase

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