Identification and characterization of a new pair of immunoglobulin-like receptors LMIR1 and 2 derived from murine bone marrow-derived mast cells

Kumagai, Hidetoshi; Oki, Toshihiko; Tamitsu, Kaori; Feng, Si Zhou; Ono, M.; Nakajima, Hitoshi; Bao, Ying; Kawakami, Yuko; Nagayoshi, Kikuko; Copeland, Neal G.; Gilbert, Debra J.; Jenkins, Nancy A.; Kawakami, Toshiaki; Kitamura, Toshio

doi:10.1016/s0006-291x(03)01245-2

Cited by 59 publications

(88 citation statements)

References 43 publications

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“…4) is shared by few other, if any, ITIM-containing receptors; and therefore, MICL is likely to have a role distinct from those of other myeloid inhibitory molecules. Other human ITIM-containing receptors expressed on PMNs/monocytes as (49), and LMIR1 (50). These inhibitory receptors have been implicated in apoptosis (51), allergy (52), autoimmune disease (53), and cancer (54,55).…”

Section: Micl Is Highly Glycosylated and Is Expressed At The Cell Surmentioning

confidence: 99%

Identification and Characterization of a Novel Human Myeloid Inhibitory C-type Lectin-like Receptor (MICL) That Is Predominantly Expressed on Granulocytes and Monocytes

Marshall

Willment

Lin

et al. 2004

Journal of Biological Chemistry

137

182

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Inhibitory and activatory C-type lectin-like receptors play an important role in immunity through the regulation of leukocytes. Here, we report the identification and characterization of a novel myeloid inhibitory Ctype lectin-like receptor (MICL) whose expression is primarily restricted to granulocytes and monocytes. This receptor, which contains a single C-type lectin-like domain and a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, is related to LOX-1 (lectin-like receptor for oxidized low density lipoprotein-1) and the ␤-glucan receptor (Dectin-1) and is variably spliced and highly N-glycosylated. We demonstrate that it preferentially associates with the signaling phosphatases SHP-1 and SHP-2, but not with SHIP. Novel chimeric analyses with a construct combining MICL and the ␤-glucan receptor show that MICL can inhibit cellular activation through its cytoplasmic immunoreceptor tyrosine-based inhibitory motif. These data suggest that MICL is a negative regulator of granulocyte and monocyte function.The functional balance of the immune system is regulated, in part, by inhibitory and activatory receptors found on all leukocytes as well as on many non-immune cells (1). Within these activatory and inhibitory receptor families, cytoplasmic consensus motifs have been identified and shown to associate with particular signaling mechanisms. These motifs include the immunoreceptor tyrosine-based activation motifs (ITAMs), 1 which become phosphorylated upon stimulation, sending their activatory signals through a variety of intracellular enzyme cascades and resulting in a wide range of cellular outcomes, and the immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which suppress such activatory signals by recruiting phosphatase enzymes that dephosphorylate ITAMs as well as other components of the activatory pathways.The array of inhibitory and activatory receptors expressed by natural killer cells has recently been the focus of much investigation (2). In humans, these receptors can be divided into two families: the Ig superfamily, including the killer cell Ig-like receptors (3) that bind classical major histocompatibility complex class I or HLA G (non-classical), and the C-type lectin-like family (4), including the NKG2 receptors, which bind the nonclassical HLA E or other distantly related molecules that are up-regulated on stressed, transformed, or infected cells (5, 6).The C-type lectin and lectin-like proteins are classified into 14 groups based on the arrangement of their C-type lectin-like domains (CTLDs).2 In particular, group V receptors include the lectin-like NKG2 family mentioned above, but also a distinct subgroup of these receptors that are expressed predominantly on myeloid and endothelial cells (7). The members of this subgroup appear to bind diverse ligands, as exemplified by LOX-1 (lectin-like receptor for oxidized low density lipoprotein-1) (8) and the ␤-glucan receptor (BGR), which is an activatory phagocytic receptor for ␤-glucans (9).3 Although they share structuralhomologywithclassic...

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Section: Micl Is Highly Glycosylated and Is Expressed At The Cell Surmentioning

confidence: 99%

Identification and Characterization of a Novel Human Myeloid Inhibitory C-type Lectin-like Receptor (MICL) That Is Predominantly Expressed on Granulocytes and Monocytes

Marshall

Willment

Lin

et al. 2004

Journal of Biological Chemistry

137

182

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“…In humans, KARAP/DAP12 and KIR-S are expressed by CD4 + CD28 -T cells, which expand in patients suffering from chronic inflammatory diseases [25,26]. The activating NK cell receptor Ly49D can be expressed in immature mouse B lymphocytes, whereas myeloid associated immunoglobulin-like receptor II (MAIR-II), also known as leukocyte mono-Ig-like receptor 2 (LMIR-2), is present in LPSstimulated mouse B cells as well as in a subset of mouse peritoneal macrophages [27][28][29]. In T and B lymphocytes, KARAP/DAP12 is preferentially expressed by cells with an activated phenotype that is often related to inflammatory conditions.…”

Section: Karap/dap12 In T and B Lymphocytesmentioning

confidence: 99%

“…IREM-2 has been recently characterized in human monocytes and DC [44]. In basophils and mast cells, KARAP/DAP12-dependent receptors, such as the activating receptors CD200R3 and LMIR-2/MAIR-II, have also been recently identified but their biological role is still to be unraveled [29,45].…”

Section: Karap/dap12 In T and B Lymphocytesmentioning

confidence: 99%

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

2005

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The signaling adaptor protein KARAP/DAP12/TYROBP (killer cell activating receptorassociated protein / DNAX activating protein of 12 kDa / tyrosine kinase binding protein) belongs to the family of transmembrane polypeptides bearing an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). This adaptor, initially characterized in NK cells, is associated with multiple cell-surface activating receptors expressed in both lymphoid and myeloid lineages. We review here the main features of KARAP/DAP12, describing findings from its identification to recently published data, showing its involvement in a broad array of biological functions. KARAP/DAP12 is a wiring component for NK cell anti-viral function (e.g. mouse cytomegalovirus via its association with mouse Ly49H) and NK cell anti-tumoral function (e.g. via its association with mouse NKG2D or human NKp44). KARAP/DAP12 is also involved in inflammatory reactions via its coupling to myeloid receptors, such as the triggering receptors expressed by myeloid cells (TREM) displayed by neutrophils, monocytes/ macrophages and dendritic cells. Finally, bone remodeling and brain function are also dependent upon the integrity of KARAP/DAP12 signals, as shown by the analysis of KARAP/DAP12-deficient mice and KARAP/DAP12-deficient Nasu-Hakola patients. IntroductionPolypeptides that bear at least one immunoreceptor tyrosine-based activation motif (ITAM; YxxL-x 7 -YxxL) in their intracytoplasmic domain constitute family of various signaling molecules ( Fig. 1A and B). ITAM were first identified in the immune system, where they are required for the expression and signaling of several activating immunoreceptors, thus playing a key role in immune responses. ITAM-bearing proteins can also be detected in non-hematopoietic tissues, such as the brain, and they can also be produced by several viruses (Fig. 1A and B). The latest ITAM-bearing polypeptide to be identified [1][2][3][4][5] protein (TYROBP); here we refer to it as KARAP/DAP12. As previously described for other ITAM-bearing polypeptides, tyrosine residues present in KARAP/DAP12 ITAM, once phosphorylated, are both required for the recruitment and the activation of Syk and ZAP70, which are SH2-domain-containing protein tyrosine kinases (PTK) [3]. KARAP/DAP12 transcripts are present in bony fishes, rodents, swine and humans, showing the broad conservation of this signaling component in vertebrates [2, 3, 6, 7]. KARAP/DAP12 expression is detectable in both lymphoid and myeloid cells, where it can associate with several activating immunoreceptors, contributing to several biological functions [8].In this review, we will correlate KARAP/DAP12 broad expression in both hematopoietic and non-hematopoietic tissues with pleiotropic functions of this signaling , protein G1 of hantavirus (sequence indicated corresponds to substrain NY1, but G1 proteinITAM sequences of several other hantavirus substrains' have also been reported) [59]. All the ITAM motifs reported here, except for viral molecules, are derived from human sequenc...

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“…Paired immune receptors are generally composed of several activating and inhibitory receptors with high homology in the extracellular domains (1,2). We have previously characterized leukocyte mono-Ig-like receptors 1-5 (LMIR1-5) 3 among a novel paired receptor family called LMIR/CMRF-35-like molecules (CLMs)/myeloid-associated Ig-like receptor (MAIR)/ dendritic cell-derived Ig-like receptor (DIgR)/CD300 (3)(4)(5)(6)(7)(8)(9). LMIR3/CLM-1/MAIR-V/DIgR2/CD300LF is an inhibitory receptor that possesses an ITIM in the cytoplasmic region (4,6,7,10,11).…”

mentioning

confidence: 99%

An Activating and Inhibitory Signal from an Inhibitory Receptor LMIR3/CLM-1: LMIR3 Augments Lipopolysaccharide Response through Association with FcRγ in Mast Cells

Izawa

Kitaura

Yamanishi

et al. 2009

The Journal of Immunology

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Leukocyte mono-Ig-like receptor 3 (LMIR3) is an inhibitory receptor mainly expressed in myeloid cells. Coengagement of FcεRI and LMIR3 impaired cytokine production in bone marrow-derived mast cells (BMMCs) induced by FcεRI crosslinking alone. Mouse LMIR3 possesses five cytoplasmic tyrosine residues (Y241, Y276, Y289, Y303, Y325), among which Y241 and Y289 (Y241/289) or Y325 fit the consensus sequence of ITIM or immunotyrosine-based switch motif (ITSM), respectively. The inhibitory effect was abolished by the replacement of Y325 in addition to Y241/289 with phenylalanine (Y241/189/325/F) in accordance with the potential of Y241/289/325 to cooperatively recruit Src homology region 2 domain-containing phosphatase 1 (SHP)-1 or SHP-2. Intriguingly, LMIR3 crosslinking alone induced cytokine production in BMMCs expressing LMIR3 (Y241/276/289/303/325F) mutant as well as LMIR3 (Y241/289/325F). Moreover, coimmunoprecipitation experiments revealed that LMIR3 associated with ITAM-containing FcRγ. Analysis of FcRγ-deficient BMMCs demonstrated that both Y276/303 and FcRγ played a critical role in the activating function of this inhibitory receptor. Importantly, LMIR3 crosslinking enhanced cytokine production of BMMCs stimulated by LPS, while suppressing production stimulated by other TLR agonists or stem cell factor. Thus, an inhibitory receptor LMIR3 has a unique property to associate with FcRγ and thereby functions as an activating receptor in concert with TLR4 stimulation.

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Identification and characterization of a new pair of immunoglobulin-like receptors LMIR1 and 2 derived from murine bone marrow-derived mast cells

Cited by 59 publications

References 43 publications

Identification and Characterization of a Novel Human Myeloid Inhibitory C-type Lectin-like Receptor (MICL) That Is Predominantly Expressed on Granulocytes and Monocytes

Identification and Characterization of a Novel Human Myeloid Inhibitory C-type Lectin-like Receptor (MICL) That Is Predominantly Expressed on Granulocytes and Monocytes

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

An Activating and Inhibitory Signal from an Inhibitory Receptor LMIR3/CLM-1: LMIR3 Augments Lipopolysaccharide Response through Association with FcRγ in Mast Cells

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