Fc Receptor γ Chain Residues at the Interface of the Cytoplasmic and Transmembrane Domains Affect Association with FcαRI, Surface Expression, and Function

Wines, Bruce D.; Trist, Halina M.; Monteiro, Renato C.; Kooten, Cees van; Hogarth, P. Mark

doi:10.1074/jbc.m403684200

Cited by 21 publications

(25 citation statements)

References 61 publications

(47 reference statements)

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Section: Methodsmentioning

confidence: 99%

“…Transduction of IIA1.6 Cells for Receptor Expression-The murine B cell line IIA1.6 lacking endogenous Fc receptors (25) was transduced with recombinant retrovirus produced using the packaging line Phoenix (26) as described previously (21). Briefly, infection was with recombinant retrovirus expressing the WT or mutant FcR␥, and flow cytometry was used to select for equivalent expression of the WT and mutant FcR␥ cDNAs.…”

Section: Methodsmentioning

confidence: 99%

“…The DNA constructs WT human FcR␥ chain in pMXI-EGFP (pBAR292) and Fc␣RI in pMXpuro (pBAR252) were as described previously (21). Human Fc⑀RI in pMXpuro (pBAR286) was constructed by releasing the Fc⑀RI-encoding insert from pCK3 (24) with EcoRI and SalI, "blunt ending" with Klenow, and ligating into the SnAB I site of pMXpuro.…”

Section: Methodsmentioning

confidence: 99%

“…Receptors-Cell surface expression of Fc⑀RI␣ or Fc␣RI was measured using mouse IgE myeloma TIB142 (ATCC, Manassas, VA) or phycoerythrin-conjugated mAb A59 Pharmingen, respectively, as described previously (21). Analysis of variance using a Dunnett multiple comparison test was performed with the program GraphPad Instat (GraphPad Software Inc., San Diego, CA) and compared the levels of Fc⑀RI expression in cells expressing mutant FcR␥ subunits with the levels in cells expressing WT FcR␥ subunit.…”

Section: Facs Analysis Of Cells Expressing Fcmentioning

confidence: 99%

“…The mutations Y8F, L14A, F15A, Y17F, I19A, and L21A in FcR␥ and the mutations L215A, L217A, L220A, and L224A in Fc␣RI were introduced by splice-overlap extension using standard molecular biology techniques or by QuickChange mutagenesis (Stratagene, La Jolla, CA). The Y25F and C26S mutant FcR␥ has been described previously (21).Transduction of IIA1.6 Cells for Receptor Expression-The murine B cell line IIA1.6 lacking endogenous Fc receptors (25) was transduced with recombinant retrovirus produced using the packaging line Phoenix (26) as described previously (21). Briefly, infection was with recombinant retrovirus expressing the WT or mutant FcR␥, and flow cytometry…”

mentioning

confidence: 99%

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A Common Site of the Fc Receptor γ Subunit Interacts with the Unrelated Immunoreceptors FcαRI and FcϵRI

Wines

Trist

Ramsland

et al. 2006

Journal of Biological Chemistry

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The transmembrane (TM) region of the Fc receptor-␥ (FcR␥) chain is responsible for the association of this ubiquitous signal transduction subunit with many immunoreceptor ligand binding chains, making FcR␥ key to a number of leukocyte activities in immunity and disease. Some receptors contain a TM arginine residue that interacts with Asp-11 of the FcR␥ subunit, but otherwise the molecular basis for the FcR␥ subunit interactions is largely unknown. This study reports residues in the TM region of the FcR␥ subunit are important for association with the high affinity IgE receptor Fc⑀RI and a leukocyte receptor cluster member, the IgA receptor Fc␣RI. FcR␥ residue Leu-21 was essential for surface expression of Fc⑀RI␣/␥ 2 and Tyr-8, Leu-14, and Phe-15 contributed to expression. Likewise, detergent-stable FcR␥ association with Fc␣RI was also dependent on Leu-14 and Leu-21 and in addition required residues Tyr-17, Tyr-25, and Cys-26. Modeling the TM regions of the FcR␥ dimer indicated these residues interacting with both Fc␣RI and Fc⑀RI are near the interface between the two FcR␥ TM helices. Furthermore, the FcR␥ residues interacting with Fc␣RI form a leucine zipper-like interface with mutagenesis confirming a complementary interface comprising Fc␣RI residues Leu-217, Leu-220, and Leu-224. The dependence of these two nonhomologous receptor interactions on FcR␥ Leu-14 and Leu-21 suggests that all the associated Fc receptors and the activating leukocyte receptor cluster members interact with this one site. Taken together these data provide a molecular basis for understanding how disparate receptor families assemble with the FcR␥ subunit.The Fc receptor ␥ subunit (FcR␥) 2 is a ubiquitous signal transduction subunit widely found in hematopoietic cells and is present on macrophages, monocytes, dendritic cells, natural killer cells, platelets, eosinophils, mast cells, ␥␦ T cells, and CD4 ␣␤ effector T cells (1, 2). It is a promiscuous receptor subunit originally identified as a subunit of the high affinity IgE receptor Fc⑀RI (3) but is also associated with the ␥␦ TCR (4), the ␣␤ TCR (1, 2), DCAR (a novel C-type lectin immunoreceptor expressed on DC) (5, 6), mouse NKRP1A/C/F (7), NKp46 (8), the high affinity IgG receptor Fc␥RI (9), the low affinity IgG receptor Fc␥RIIIa (10), and the IgA receptor Fc␣RI (11,12). Fc␣RI, although a functional FcR, is a member of the leukocyte receptor cluster (LRC) whose genes are all encoded at 19q13.4 (13). A potentially charged TM residue in the Ig superfamily receptors is generally indicative of assembly with a small signal transduction molecule (14). The activating LRC receptors, Fc␣RI (11,12,15), the leukocyte Ig-like receptor A2 (LILR-A2, LIR7, ILT-1) (16), and the platelet collagen receptor glycoprotein VI (17, 18), NKp46 (8), and OSCAR (6), contain a TM arginine residue essential for interaction with FcR␥. Other than the TM arginine residue, it is not known if other TM residues of the activating LRC receptors are important in interacting with FcR␥. The TM regions of the FcRs, Fc⑀RI, Fc␥...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Facs Analysis Of Cells Expressing Fcmentioning

confidence: 99%

mentioning

confidence: 99%

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A Common Site of the Fc Receptor γ Subunit Interacts with the Unrelated Immunoreceptors FcαRI and FcϵRI

Wines

Trist

Ramsland

et al. 2006

Journal of Biological Chemistry

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Enhanced FcαRI‐mediated neutrophil migration towards tumour colonies in the presence of endothelial cells

et al. 2012

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Neutrophils potently kill tumour cells in the presence of anti-tumour antibodies in vitro.However, for in vivo targeting, the neutrophils need to extravasate from the circulation by passing through endothelial barriers. To study neutrophil migration in the presence of endothelial cells in vitro, we established a three-dimensional collagen culture in which SK-BR-3 tumour colonies were grown in the presence or absence of an endothelial barrier. We demonstrated that -in contrast to targeting FcγR on neutrophils with mAbstargeting the immunoglobulin A Fc receptor (FcαRI) instead triggered neutrophil migration and degranulation leading to tumour destruction, which coincided with release of the pro-inflammatory cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α. Interestingly, neutrophil migration was enhanced in the presence of endothelial cells, which coincided with production of significant levels of the neutrophil chemokine IL-8. This supports the idea that stimulation of neutrophil FcαRI, but not FcγR, initiates crosstalk between neutrophils and endothelial cells, leading to enhanced neutrophil migration towards tumour colonies and subsequent tumour killing.Keywords: Bispecific antibody r Chemotaxis immunotherapy r HUVEC r IgA IntroductionNeutrophils represent the most populous type of cytotoxic effector cells within the blood and their numbers can easily be increased by treatment with granulocyte colony-stimulating factor (G-CSF) [1]. Because depletion of these cells resulted in increased tumour outgrowth in animal models, neutrophils may play a role in tumour Immunol. 2012Immunol. . 42: 1815Immunol. -1821 Importantly, anti-tumour monoclonal antibodies (mAbs) or bispecific Abs (BsAbs) -which link Fc receptors on immune cells and tumour-associated antigens (TAAs) on tumour cells -enhance neutrophil-mediated tumour cell lysis [8][9][10]. Initially, the immunoglobulin (Ig) G receptor FcγRI was proposed as a potent target for initiation of neutrophil-induced Ab-mediated tumour cell lysis. In recent years, however, it was demonstrated that targeting the IgA Fc receptor (FcαRI) resulted in more effective neutrophil-mediated Ab-dependent tumour cell lysis [11][12][13][14][15][16][17][18][19]. Furthermore, killing was initiated through non-apoptotic pathways, which coincided with autophagic characteristics [20]. Moreover, triggering of FcαRI induced recruitment of neutrophils into tumour colonies [9]. We recently demonstrated that IgA induced significant release of the neutrophil chemoattractant leukotriene B 4 (LTB 4 ) [21]. Thus, neutrophils represent interesting effector cells for Ab immunotherapy of cancer. However, in order to achieve Ab-mediated lysis of solid tumours in vivo, neutrophils need to extravasate from the circulation into the tumour. Therefore, we now investigated Ab-induced neutrophil migration towards tumour colonies in the presence of an endothelial cell barrier. Results and discussion Targeting FcαRI induces migration, degranulation and release of pro-inflammatory cytokinesNeutroph...

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Signaling Chain Homooligomerization (SCHOOL) Model

Sigalov

Advances in Experimental Medicine and Biology

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Multichain immune recognitionreceptors (MIRRs) represent a family of surfacereceptors expressed on different cells of the hematopoietic system and function to transduce signals leading to a variety of biologic responses. The most intriguing and distinct structural feature ofMIRR family members is that extracellular recognition domains and intracellular signaling domains are located on separate subunits. The biochemical cascades triggered by MIRRs are understood in significant detail, however, the mechanism by which extracellular ligand binding initiates intracellular signal transduction processes is not clear and no model fully explains how MIRR signaling commences. In this Chapter, I describe a novel mechanistic model of MIRR-mediated signal transduction, the signaling chain homooligomerization (SCHOOL) model. The basic concept of this model assumes that the structural similarity of the MIRRs provides the basis for the similarity in the mechanisms ofMIRR-mediated transmembrane signaling. Within the SCHOOL model, MIRR triggering is considered to be a result of the ligand-induced interplay between (1) intrareceptor transmembrane interactions between MIRR recognition and signaling subunits that stabilize and maintain receptor integrity and (2) interreceptor homointeractions between MIRR signaling subunits that lead to the formation of oligomeric signaling structures, thus triggering the receptors and initiating the signaling cascade. Thus, the SCHOOL model is based on specific protein-protein interactions--biochemical processes that can be influenced and controlled. In this context, this plausible and easily testable model is fundamentally different from those previously suggested for particular MIRRs and has several important advantages. The basic principles oftransmembrane signaling learned from the SCHOOL model may be used in different fields of immunology and cell biology to describe, explain and predict immunological phenomena and processes mediated by structurally related but functionally different membrane receptors. Important applications of the SCHOOL model in clinical immunology, molecular pharmacology and virology are described in the Chapters 20 and 22 of this book.

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Fc Receptor γ Chain Residues at the Interface of the Cytoplasmic and Transmembrane Domains Affect Association with FcαRI, Surface Expression, and Function

Cited by 21 publications

References 61 publications

A Common Site of the Fc Receptor γ Subunit Interacts with the Unrelated Immunoreceptors FcαRI and FcϵRI

A Common Site of the Fc Receptor γ Subunit Interacts with the Unrelated Immunoreceptors FcαRI and FcϵRI

Enhanced FcαRI‐mediated neutrophil migration towards tumour colonies in the presence of endothelial cells

Signaling Chain Homooligomerization (SCHOOL) Model

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