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W1993934534 abstract "Paired Ig-like receptors (PIR) are polymorphic type I transmembrane proteins belonging to an Ig superfamily encoded by multiple isotypic genes. They are expressed on immune cells such as mast cells, macrophages, and B lymphocytes. Two subtypes of PIR have been classified according to the difference in the primary structure of the PIR transmembrane and cytoplasmic regions. These subtypes are designated as PIR-A and PIR-B. In this study, the transmembrane and cytoplasmic regions of the PIR-A subtype were shown to mediate activation signal events such as cytoplasmic calcium mobilization, protein tyrosine phosphorylations, and degranulation in rat mast cell line RBL-2H3. The association of the Fc receptor γ and β subunits with PIR-A was shown to be responsible for PIR-A function but not required for membrane expression of PIR-A on COS-7 cells. We further revealed the role of two charged amino acid residues in the transmembrane region, namely arginine and glutamic acid, in PIR-A function and its association with the above subunits. In contrast to the inhibitory nature of the PIR-B subtype, present findings reveal that PIR-A potentially acts as a stimulatory receptor in mast cells, suggesting a mechanism for regulation of mast cell functions by the PIR family. Paired Ig-like receptors (PIR) are polymorphic type I transmembrane proteins belonging to an Ig superfamily encoded by multiple isotypic genes. They are expressed on immune cells such as mast cells, macrophages, and B lymphocytes. Two subtypes of PIR have been classified according to the difference in the primary structure of the PIR transmembrane and cytoplasmic regions. These subtypes are designated as PIR-A and PIR-B. In this study, the transmembrane and cytoplasmic regions of the PIR-A subtype were shown to mediate activation signal events such as cytoplasmic calcium mobilization, protein tyrosine phosphorylations, and degranulation in rat mast cell line RBL-2H3. The association of the Fc receptor γ and β subunits with PIR-A was shown to be responsible for PIR-A function but not required for membrane expression of PIR-A on COS-7 cells. We further revealed the role of two charged amino acid residues in the transmembrane region, namely arginine and glutamic acid, in PIR-A function and its association with the above subunits. In contrast to the inhibitory nature of the PIR-B subtype, present findings reveal that PIR-A potentially acts as a stimulatory receptor in mast cells, suggesting a mechanism for regulation of mast cell functions by the PIR family. paired Ig-like receptor FcεR, and FcγR, Fc receptors for IgA, IgE, and IgG, respectively γ and β subunits of the high affinity Fc receptor for IgE, respectively interleukin Ig-like transcript leukocyte Ig-like receptor polymerase chain reaction Paired Ig-like receptor (PIR)1 (1Hayami K. Fukuta D. Nishikawa Y. Yamashita Y. Inui M. Ohyama Y. Hikida M. Ohmori H. Takai T. J. Biol. Chem. 1997; 272: 7320-7327Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 2Kubagawa H. Burrows P.D. Cooper M.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5261-5266Crossref PubMed Scopus (270) Google Scholar) has recently been found to be a murine receptor analogous to human Fc receptor for IgA (FcαR), although its binding capacity for murine IgA has not been shown. Analyses of a number of cDNA sequences and genomic clones for PIR revealed a gene family consisting of at least three isotypic genes (3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar). Its structural features have been determined to consist of type I transmembrane glycoprotein with six conserved Ig-like domains followed by two distinct amino acid sequences encompassing the transmembrane to cytoplasmic region. These amino acid sequences serve as the basis for classification of PIR into two subtypes, PIR-A and PIR-B (2Kubagawa H. Burrows P.D. Cooper M.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5261-5266Crossref PubMed Scopus (270) Google Scholar, 3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar). mRNA expression for both subtypes has been detected in B cells, interleukin-3-induced bone marrow mast cells, and myelomonocytic lineage cells (2Kubagawa H. Burrows P.D. Cooper M.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5261-5266Crossref PubMed Scopus (270) Google Scholar, 3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar). PIR is currently thought to be a murine receptor homologous to the human receptor ILT/LIR because of the similarity of their primary structures (3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar, 4Samaridis J. Colonna M. Eur. J. Immunol. 1997; 27: 660-665Crossref PubMed Scopus (252) Google Scholar), their expression patterns in immune cell types except for NK cells (5Cella M. Döhring C. Samaridis J. Dessing M. Brockhaus M. Lanzavecchia A. Colonna M. J. Exp. Med. 1997; 185: 1743-1751Crossref PubMed Scopus (353) Google Scholar, 6Cosman D. Fanger N. Borges L. Kubin M. Chin W. Peterson L. Hsu M.-L. Immunity. 1997; 7: 273-282Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar), the polymorphic nature of their isotypes (4Samaridis J. Colonna M. Eur. J. Immunol. 1997; 27: 660-665Crossref PubMed Scopus (252) Google Scholar, 5Cella M. Döhring C. Samaridis J. Dessing M. Brockhaus M. Lanzavecchia A. Colonna M. J. Exp. Med. 1997; 185: 1743-1751Crossref PubMed Scopus (353) Google Scholar, 6Cosman D. Fanger N. Borges L. Kubin M. Chin W. Peterson L. Hsu M.-L. Immunity. 1997; 7: 273-282Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 7Torkar M. Norgate Z. Colonna M. Trowsdale J. Wilson M.J. Eur. J. Immunol. 1998; 28: 3959-3967Crossref PubMed Scopus (98) Google Scholar), and chromosomal locations (3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar, 8Wagtmann N. Rojo S. Eichler E. Mohrenweiser H. Long E.O. Curr. Biol. 1997; 7: 615-618Abstract Full Text Full Text PDF PubMed Google Scholar, 9Arm J.P. Nwankwo C. Austen K.F. J. Immunol. 1997; 159: 2342-2349PubMed Google Scholar). Recent studies have demonstrated inhibitory function and recognition for human major histocompatibility complex class I and virus-related major histocompatibility complex class I-like proteins by some isotypes of the ILT/LIR family, suggesting a regulatory function of ILT/LIR for immune responses in the context of major histocompatibility complex class I recognition as in the case of killer cell inhibitory receptor (6Cosman D. Fanger N. Borges L. Kubin M. Chin W. Peterson L. Hsu M.-L. Immunity. 1997; 7: 273-282Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 10Colonna M. Navarro F. Bellón T. Llano M. Garcı́a P. Samaridis J. Angman L. Cella M. López-Botet M. J. Exp. Med. 1997; 186: 1809-1818Crossref PubMed Scopus (783) Google Scholar). PIR-B was shown to function as an inhibitory receptor, whereas the functions of PIR-A and ligands of the entire PIR family remain unknown.The main feature of PIR-B subtype is to harbor the conserved amino acid motifs in a cytoplasmic region denoted as immunoreceptor tyrosine-based inhibitory motif. Inhibitory function of PIR-B has been shown in splenic B cells (11Bléry M. Kubagawa H. Chen C. Vély F. Cooper M.D. Vivier E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2446-2451Crossref PubMed Scopus (176) Google Scholar), a B cell line (12Maeda A. Kurosaki M. Ono M. Takai T. Kurosaki T. J. Exp. Med. 1998; 187: 1355-1360Crossref PubMed Scopus (171) Google Scholar), and a mast cell line (13Yamashita Y. Ono M. Takai T. J. Immunol. 1998; 161: 4042-4047PubMed Google Scholar), and the two immunoreceptor tyrosine-based inhibitory motifs of the PIR-B cytoplasmic region have been proven to exert inhibitory signaling by recruiting protein-tyrosine phosphatase, SHP-1 or SHP-2, which commonly functions as the signal transducer of immunoreceptor tyrosine-based inhibitory motif-based receptors including killer cell inhibitory receptor (14Olcese L. Lang P. Vély F. Cambiaggi A. Marguet D. Bléry M. Hippen K.L. Biassoni R. Moretta A. Moretta L. Cambier J.C. Vivier E. J. Immunol. 1996; 156: 4531-4534PubMed Google Scholar, 15Campbell K.S. Dessing M. López-Botet M. Cella M. Colonna M. J. Exp. Med. 1996; 184: 93-100Crossref PubMed Scopus (194) Google Scholar, 16Fry A.M. Lanier L.L. Weiss A. J. Exp. Med. 1996; 184: 295-300Crossref PubMed Scopus (187) Google Scholar, 17Binstadt B.A. Brumbaugh K.M. Dick C.J. Scharenberg A.M. Williams B.L. Colonna M. Lanier L.L. Kinet J.-P. Abraham R.T. Leibson P.J. Immunity. 1996; 5: 629-638Abstract Full Text PDF PubMed Scopus (258) Google Scholar), Ly-49 (18Nakamura M.C. Niemi E.C. Fisher M.J. Shultz L.D. Seaman W.E. Ryan J.C. J. Exp. Med. 1997; 185: 673-684Crossref PubMed Scopus (189) Google Scholar), NKG2 (19Dréan E.L. Vély F. Olcese L. Cambiaggi A. Guia S. Krystal G. Gervois N. Moretta A. Jotereau F. Vivier E. Eur. J. Immunol. 1998; 28: 264-276Crossref PubMed Scopus (191) Google Scholar), CD22 (20Campbell M.A. Klinman N.R. Eur. J. Immunol. 1995; 25: 1573-1579Crossref PubMed Scopus (112) Google Scholar, 21Doody G.M. Justement L.B. Delibrias C.C. Matthews R.J. Lin J. Thomas M.L. Fearon D.T. Science. 1995; 269: 242-244Crossref PubMed Scopus (483) Google Scholar, 22Lankester A.C. van Schijndel G.M. van Lier R.A. J. Biol. Chem. 1995; 270: 20305-20308Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 23Law C.L. Sidorenko S.P. Chandran K.A. Zhao Z. Shen S.H. Fischer E.H. Clark E.A. J. Exp. Med. 1996; 183: 547-560Crossref PubMed Scopus (176) Google Scholar), and ILT/LIR (5Cella M. Döhring C. Samaridis J. Dessing M. Brockhaus M. Lanzavecchia A. Colonna M. J. Exp. Med. 1997; 185: 1743-1751Crossref PubMed Scopus (353) Google Scholar, 6Cosman D. Fanger N. Borges L. Kubin M. Chin W. Peterson L. Hsu M.-L. Immunity. 1997; 7: 273-282Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 10Colonna M. Navarro F. Bellón T. Llano M. Garcı́a P. Samaridis J. Angman L. Cella M. López-Botet M. J. Exp. Med. 1997; 186: 1809-1818Crossref PubMed Scopus (783) Google Scholar). The inhibitory nature of PIR-B led us to postulate a role of PIR signaling in regulation of immune responses involving mast cells, B cells, and macrophages.PIR-A is defined as a group of noninhibitory type of PIR family receptors characterized by a short cytoplasmic region that is free of any consensus amino acid sequence for activation. Instead, the transmembrane region of PIR-A harbors positively and negatively charged amino acid residues (see Fig. 7). Transmembrane-charged residues can typically be seen in stimulatory receptors mediating a variety of immune responses, such as T cell receptor, the ligand binding α chains of type I and type III Fc receptors for IgG (FcγRIα and FcγRIIIα, respectively), FcαR, killer cell inhibitory receptor-2DS/3DS (alternatively called KAR), and NKR-P1 (CD161). All of these themselves have no amino acid motif for activation but associate with signaling subunits such as CD3 complex, γ and β chains (FcRγ and FcRβ, respectively) of type I FcR for IgE (FcεRI), and DAP12 (24Ravetch J.V. Kinet J.-P. Annu. Rev. Immunol. 1991; 9: 457-492Crossref PubMed Scopus (1273) Google Scholar, 25Pfefferkorn L.C. Yeaman G.R. J. Immunol. 1994; 153: 3228-3236PubMed Google Scholar, 26Saito K. Suzuki K. Matsuda H. Okumura K. Ra C. J. Allergy Clin. Immunol. 1995; 96: 1152-1160Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 27Arase N. Arase H. Park S.Y. Ohno H. Ra C. Saito T. J. Exp. Med. 1997; 186: 1957-1963Crossref PubMed Scopus (133) Google Scholar, 28Lanier L.L. Corliss B.C. Wu J. Leong C. Phillps J.H. Nature. 1998; 391: 703-707Crossref PubMed Scopus (736) Google Scholar) to generate an activation signal in response to receptor aggregation. Previous studies on T cell receptor α chain and FcαR have demonstrated the requirement of a positively charged amino acid residue in the transmembrane region for their function and subunit association (29Manolios N. Bonifacino J.S. Klausner R.D. Science. 1990; 249: 274-277Crossref PubMed Scopus (190) Google Scholar, 30Morton H.C. van den Herik-Oudijk I.E. Vossebeld P. Snijders A. Verhoeven A.J. Capel P.J. van de Winkel J.G.J. J. Biol. Chem. 1995; 270: 29781-29787Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). The presence of charged amino acid residues in the transmembrane region of PIR-A suggests the possibility that PIR-A associates with activation subunits to deliver an activation signal into the cell. Our recent observations have suggested that one of the PIR-A isotypes, previously denoted by p91D, mediates the activation signal revealed by cytoplasmic calcium mobilization and degranulation in mast cell line (13Yamashita Y. Ono M. Takai T. J. Immunol. 1998; 161: 4042-4047PubMed Google Scholar).The present study focuses on the following two points. The first point is the mechanism of PIR-A function, and the second point is the evaluation of the role in PIR-A function of two charged amino acid residues present in the PIR-A transmembrane region. We have shown that the association of homodimeric FcRγ chains and FcRβ enable PIR-A to generate an activation signal in a mast cell line and that the charged amino acid residues contribute to the subunit association and stimulatory function of PIR-A.DISCUSSIONThe present results demonstrate the potent stimulatory function of PIR-A in mast cell line RBL-2H3, and the association of FcRβ as well as homodimeric FcRγ with PIR-A to activate the signaling pathway shared with FcεRI and FcγRIII. Our results also confirmed the recently reported FcRγ association with PIR-A (39Maeda A. Kurosaki M. Kurosaki T. J. Exp. Med. 1998; 188: 991-995Crossref PubMed Scopus (89) Google Scholar, 40Kubagawa H. Chen C.-C. Ho L.H. Shimada T. Gartland L. Mashburn C. Uehara T. Ravetch J.V. Cooper M.D. J. Exp. Med. 1999; 189: 309-318Crossref PubMed Scopus (125) Google Scholar). Previous studies on FcRγ-deficient mice have demonstrated that mast cells were affected in effector functions but not in ontogeny (40Kubagawa H. Chen C.-C. Ho L.H. Shimada T. Gartland L. Mashburn C. Uehara T. Ravetch J.V. Cooper M.D. J. Exp. Med. 1999; 189: 309-318Crossref PubMed Scopus (125) Google Scholar, 42Takai T. Li M. Sylvestre D. Clynes R. Ravetch J.V. Cell. 1994; 76: 519-529Abstract Full Text PDF PubMed Scopus (817) Google Scholar), suggesting that PIR-A may not be involved in a developmental signal to support the differentiation of mast cells. Thus, physiological PIR-A functions are discussed in relation to effector functions of mast cells. Several lines of evidence based on recent experiments in vivo have indicated that FcεRI and FcγRIII on mast cells play an important role in triggering distinct types of inflammatory responses such as anaphylaxis and Arthus reaction (42Takai T. Li M. Sylvestre D. Clynes R. Ravetch J.V. Cell. 1994; 76: 519-529Abstract Full Text PDF PubMed Scopus (817) Google Scholar, 43Martin T.R. Galli S.J. Katona I.M. Drazen J.M. J. Clin. Invest. 1989; 83: 1375-1383Crossref PubMed Scopus (90) Google Scholar, 44Sylvestre D.L. Ravetch J.V. Science. 1994; 265: 1095-1098Crossref PubMed Scopus (276) Google Scholar, 45Dombrowicz D. Flamand V. Brigmann K.K. Koller B.H. Kinet J.-P. Cell. 1993; 75: 969-975Abstract Full Text PDF PubMed Scopus (330) Google Scholar, 46Dombrowicz D. Flamand V. Miyajima I. Ravetch J.V. Galli S.J. Kinet J.-P. J. Clin. Invest. 1997; 99: 915-925Crossref PubMed Scopus (172) Google Scholar, 47Hazenbos W.L. Gessner J.E. Hofhuis F.M. Kuipers H. Meyer D. Heijnen I.A. Schmidt R.E. Sandor M. Capel P.J. Daëron M. van de Winkel J.G.J. Verbeek J.S. Immunity. 1996; 5: 181-188Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). Mast cell activation by these FcRs may also contribute to the development of chronic allergic syndromes in humans, examples of which include atopic syndrome and bronchial hypersensitivity, by means of activating other cell types with mast cell-derived inflammatory cytokines (48Gordon J.R. Burd P.R. Galli S.J. Immunol. Today. 1990; 11: 458-464Abstract Full Text PDF PubMed Scopus (169) Google Scholar). These allergic manifestations can presently be attributed, at least in part, to the result of up-regulation of signals by FcεRI and/or FcγRIII in mast cells. The present findings lead to the tempting possibility that PIR-A aggregation exerts an additive effect on the signal by FcRs and, consequently, that PIR-A functions as an accelerator in developing mast cell-related pathological manifestations.ILT/LIRs are thought to be the human homologue of PIR, and its mRNA expression in human lung mast cells has been reported by Arm et al. (9Arm J.P. Nwankwo C. Austen K.F. J. Immunol. 1997; 159: 2342-2349PubMed Google Scholar). The transmembranes of their noninhibitory types, ILT1/LIR7, and PIR-A express strikingly conserved primary structures (Fig. 7 A), suggesting that noninhibitory types ILT1/LIR7 associate with FcRγ and FcRβ. In fact, FcRγ association with ILT1 has been reported very recently (49Nakajima H. Samaridis J. Angman L. Colonna M. J. Immunol. 1999; 162: 5-8PubMed Google Scholar). Thus, the insight from our findings may be allowed to extend to human physiology.We have shown that PIR-A potentially acts as a stimulatory receptor, and its function relates to the association of FcRγ and FcRβ subunits in RBL-2H3 cells. Not all cell types bearing PIR-A express FcRβ subunits, i.e. monocytes and granulocytes. As in the case of Fc receptors (50Lin S. Cicala C. Scharenberg A.M. Kinet J.-P. Cell. 1996; 85: 985-995Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 51Dombrowicz D. Lin S. Flamand V. Brini A.T. Koller B.H. Kinet J.-P. Immunity. 1998; 8: 517-529Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar), FcRβ may not be necessary but may act as an accelerator for signal transduction. The role of FcRβ in PIR-A-derived signal transduction should be addressed by further investigation. The mRNA for PIR-A and PIR-B were also detected in mature B cells that are known to express neither FcRγ nor FcRβ. Based on current information, PIR-A cannot exert any stimulatory function, so that PIR-B has a dominant function over PIR-A in mature B cells. To further understand the mechanism of positive and negative regulations by PIR-A and PIR-B receptors, we also examined whether PIR-A requires subunits for its membrane expression. In contrast to FcγRIII, FcγRII-PIR-A did not require FcRγ for its membrane expression in COS-7 cells as well as human FcαR (26Saito K. Suzuki K. Matsuda H. Okumura K. Ra C. J. Allergy Clin. Immunol. 1995; 96: 1152-1160Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 30Morton H.C. van den Herik-Oudijk I.E. Vossebeld P. Snijders A. Verhoeven A.J. Capel P.J. van de Winkel J.G.J. J. Biol. Chem. 1995; 270: 29781-29787Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Our results for PIR-A expression using COS-7 cells are similar to the results in transfected 293T cells (39Maeda A. Kurosaki M. Kurosaki T. J. Exp. Med. 1998; 188: 991-995Crossref PubMed Scopus (89) Google Scholar) but different from the results in transfected LTK fibroblasts or splenocytes from FcRγ deficient mice (40Kubagawa H. Chen C.-C. Ho L.H. Shimada T. Gartland L. Mashburn C. Uehara T. Ravetch J.V. Cooper M.D. J. Exp. Med. 1999; 189: 309-318Crossref PubMed Scopus (125) Google Scholar). Because the two cell lines permissive to expression of PIR-A in the absence of FcRγ were those transformed with the gene encoding SV40 large T antigen, a high level of PIR-A translation could cause redundant accumulation of the receptor protein in these cells, resulting in membrane expression without FcRγ association. It is also possible that the FcRγ requirement for PIR-A expression might differ by cell type, although the mature cell population present in the spleen requires FcRγ for PIR-A expression (40Kubagawa H. Chen C.-C. Ho L.H. Shimada T. Gartland L. Mashburn C. Uehara T. Ravetch J.V. Cooper M.D. J. Exp. Med. 1999; 189: 309-318Crossref PubMed Scopus (125) Google Scholar). In this sense, the physiological requirement of FcRγ for PIR-A membrane expression still needs to be investigated using a highly sorted cell species.The results from mutation analyses on FcγRII-PIR-A demonstrate the role of transmembrane-charged amino acids of PIR-A, Arg626and Glu643, in subunit association and PIR-A-mediated signal transduction. Charged amino acids of the transmembrane region are commonly found in stimulatory receptors (Fig. 7). The hydrophobic nature of α helix structure is thought to be a basic requirement for membrane integration by the transmembrane region (52Kyte J. Doolittle R.F. J. Mol. Biol. 1982; 157: 105-132Crossref PubMed Scopus (16996) Google Scholar). Accordingly, the presence of charged amino acids is unfavorable for stable membrane expression. However, membrane expression of these stimulatory receptors is presently rationalized by association of a subunit bearing counter-charged transmembrane region to achieve hydrophobicity by neutralizing transmembrane charges. As shown Fig. 7 B, FcRγ distributes two charged amino acids, aspartic acid and arginine, in the transmembrane region at seemingly parallel positions to those of PIR-A with the opposite charges. Our results indicate that both Arg626 and Glu643 of PIR-A each have an effect on the binding affinity of FcRγ and FcRβ to PIR-A, supporting the existence of a mechanism for subunit assembly and specificity based on electrostatic protein interaction at a membrane site. We unexpectedly observed that the requirement of Arg626 and Glu643 for PIR-A-derived signal transduction does not parallel that for subunit association. The loss of the negative charge of Glu643 does result in a decrease of subunit association but does not affect the capacity for FcRγ phosphorylation and its downstream PIR-A-mediated function. These findings brought us to assume the following two mechanisms for AEQ2-derived signal transduction. The first was that an increase in subunit association with AEQ2 receptor took place along with receptor aggregation, and the second was that efficient phosphorylation of FcRγ was undertaken by the minor fraction of AEQ2 receptor where the subunit association was resistant to mutation. Stimulation of AEQ2 receptor was found to induce FcRγ phosphorylation in both total and AEQ2-associated FcRγ fractions to the same extent as the intact receptor, despite the fact that the amount of subunit associated with AEQ2 receptor remained much smaller than the amount of intact receptor. These findings may support the latter mechanism mentioned above and suggest the presence of a functionally competent fraction of the receptor-subunit complex in the membrane. It is important to note that our discussions were based on experiments using detergent-soluble cell fractions. Recent findings have shown the importance of detergent-insoluble fractions in signal transduction for some receptors. We did not examine whether or not AEQ2 receptor functioned in detergent-insoluble fractions. Further investigation is therefore required to understand the mechanism of receptor function and its subunit association. Paired Ig-like receptor (PIR)1 (1Hayami K. Fukuta D. Nishikawa Y. Yamashita Y. Inui M. Ohyama Y. Hikida M. Ohmori H. Takai T. J. Biol. Chem. 1997; 272: 7320-7327Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 2Kubagawa H. Burrows P.D. Cooper M.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5261-5266Crossref PubMed Scopus (270) Google Scholar) has recently been found to be a murine receptor analogous to human Fc receptor for IgA (FcαR), although its binding capacity for murine IgA has not been shown. Analyses of a number of cDNA sequences and genomic clones for PIR revealed a gene family consisting of at least three isotypic genes (3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar). Its structural features have been determined to consist of type I transmembrane glycoprotein with six conserved Ig-like domains followed by two distinct amino acid sequences encompassing the transmembrane to cytoplasmic region. These amino acid sequences serve as the basis for classification of PIR into two subtypes, PIR-A and PIR-B (2Kubagawa H. Burrows P.D. Cooper M.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5261-5266Crossref PubMed Scopus (270) Google Scholar, 3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar). mRNA expression for both subtypes has been detected in B cells, interleukin-3-induced bone marrow mast cells, and myelomonocytic lineage cells (2Kubagawa H. Burrows P.D. Cooper M.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5261-5266Crossref PubMed Scopus (270) Google Scholar, 3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar). PIR is currently thought to be a murine receptor homologous to the human receptor ILT/LIR because of the similarity of their primary structures (3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar, 4Samaridis J. Colonna M. Eur. J. Immunol. 1997; 27: 660-665Crossref PubMed Scopus (252) Google Scholar), their expression patterns in immune cell types except for NK cells (5Cella M. Döhring C. Samaridis J. Dessing M. Brockhaus M. Lanzavecchia A. Colonna M. J. Exp. Med. 1997; 185: 1743-1751Crossref PubMed Scopus (353) Google Scholar, 6Cosman D. Fanger N. Borges L. Kubin M. Chin W. Peterson L. Hsu M.-L. Immunity. 1997; 7: 273-282Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar), the polymorphic nature of their isotypes (4Samaridis J. Colonna M. Eur. J. Immunol. 1997; 27: 660-665Crossref PubMed Scopus (252) Google Scholar, 5Cella M. Döhring C. Samaridis J. Dessing M. Brockhaus M. Lanzavecchia A. Colonna M. J. Exp. Med. 1997; 185: 1743-1751Crossref PubMed Scopus (353) Google Scholar, 6Cosman D. Fanger N. Borges L. Kubin M. Chin W. Peterson L. Hsu M.-L. Immunity. 1997; 7: 273-282Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 7Torkar M. Norgate Z. Colonna M. Trowsdale J. Wilson M.J. Eur. J. Immunol. 1998; 28: 3959-3967Crossref PubMed Scopus (98) Google Scholar), and chromosomal locations (3Yamashita Y. Fukuta D. Tsuji A. Nagabukuro A. Matsuda Y. Nishikawa Y. Ohyama Y. Ohmori H. Ono M. Takai T. J. Biochem. ( Tokyo ). 1998; 123: 358-368Crossref PubMed Scopus (52) Google Scholar, 8Wagtmann N. Rojo S. Eichler E. Mohrenweiser H. Long E.O. Curr. Biol. 1997; 7: 615-618Abstract Full Text Full Text PDF PubMed Google Scholar, 9Arm J.P. Nwankwo C. Austen K.F. J. Immunol. 1997; 159: 2342-2349PubMed Google Scholar). 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