Cytokine-induced inside-out activation of FcalphaR (CD89) is mediated by a single serine residue (S263) in the intracellular domain of the receptor.

Fc receptors play an important role in leukocyte activation and the modulation of ligand binding ("activation") is a critical point of regulation. Previous studies demonstrated that the Fc receptor for IgA (FcalphaRI/CD89) is regulated by cytokine stimulation, switching it to a high-binding state. To investigate the mechanism by which cytokine-induced signal transduction pathways result in FcalphaRI activation, cell lines expressing various receptor mutants were generated. Binding studies indicated that truncation of the C-terminus of the FcalphaRI resulted in constitutive IgA binding, removing the need for cytokine stimulation. Furthermore, mutagenesis of a single C-terminal serine residue (S263) to alanine (S>A) (single-letter amino acid codes) also resulted in constitutive IgA binding, whereas a serine to aspartate (S>D) mutation was no longer functional. The role of S263 might be in regulating the interaction with the cytoskeleton, because disruption of the cytoskeleton results in reduced IgA binding to both FcalphaRwt and FcalphaR_S>A. In addition, overexpression of a membrane-targeted intracellular domain of FcalphaR, and the introduction of cell-permeable CD89 fusion proteins blocked IgA binding, implying a competition for endogenous proteins. The proposal is made that Fc receptors are activated by cytokines via an inside-out mechanism converging at the cytoplasmic tail of these receptors. (Blood. 2001;97:3478-3483)

[1]  Natalie A. Lissy,et al.  Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration , 1998, Nature Medicine.

[2]  M. Pfaff,et al.  Integrin affinity modulation. , 1998, Trends in cell biology.

[3]  C. Turck,et al.  A role for the actin-bundling protein L-plastin in the regulation of leukocyte integrin function. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[4]  S. Goodman,et al.  Transmembrane-truncated alphavbeta3 integrin retains high affinity for ligand binding: evidence for an 'inside-out' suppressor? , 1998, The Biochemical journal.

[5]  L. Koenderman,et al.  Differential effects of the T helper cell type 2-derived cytokines IL-4 and IL-5 on ligand binding to IgG and IgA receptors expressed by human eosinophils. , 1997, Journal of immunology.

[6]  P. Coffer,et al.  Granulocyte signal transduction and priming: cause without effect? , 1997, Immunology letters.

[7]  P. Coffer,et al.  Analysis of signal transduction pathways regulating cytokine-mediated Fc receptor activation on human eosinophils. , 1997, Journal of immunology.

[8]  L. Koenderman,et al.  Cloning and characterization of Fc alpha Rb, a novel Fc alpha receptor (CD89) isoform expressed in eosinophils and neutrophils. , 1996, Blood.

[9]  N. Hogg,et al.  Regulation of leukocyte integrin function: Affinity vs. avidity , 1996, Journal of cellular biochemistry.

[10]  J. Lammers,et al.  Activation of the STAT3/Acute Phase Response Factor Transcription Factor by Interleukin-5 (*) , 1995, The Journal of Biological Chemistry.

[11]  B. Burgering,et al.  Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction , 1995, Nature.

[12]  J. Ravetch.  Fc receptors: Rubor redux , 1994, Cell.

[13]  M. Cooper,et al.  Definition of immunoglobulin A receptors on eosinophils and their enhanced expression in allergic individuals. , 1993, The Journal of clinical investigation.

[14]  L. Koenderman,et al.  Granulocyte-macrophage colony-stimulating factor induces sequential activation and deactivation of binding via a low-affinity IgG Fc receptor, hFc gamma RII, on human eosinophils. , 1993, Blood.

[15]  Richard O. Hynes,et al.  Integrins: Versatility, modulation, and signaling in cell adhesion , 1992, Cell.

[16]  C. Anderson,et al.  Biology of Human Immunoglobulin G Fc Receptors , 1991, Journal of leukocyte biology.

[17]  C. March,et al.  Expression cloning of a human Fc receptor for IgA , 1990, The Journal of experimental medicine.

[18]  S. Kellie,et al.  Differential tyrosine-specific phosphorylation of integrin in Rous sarcoma virus transformed cells with differing transformed phenotypes. , 1990, Oncogene.

[19]  K. Burridge,et al.  An interaction between alpha-actinin and the beta 1 integrin subunit in vitro , 1990, The Journal of cell biology.

[20]  K. Horgan,et al.  Roles of Adhesion Molecules in T‐Cell Recognition: Fundamental Similarities between Four Integrins on Resting Human T Cells (LFA‐1, VLA‐4, VLA‐5, VLA‐6) in Expression, Binding, and Costimulation , 1990, Immunological reviews.

[21]  M. Cooper,et al.  Cellular distribution, regulation, and biochemical nature of an Fc alpha receptor in humans , 1990, The Journal of experimental medicine.

[22]  Michael L. Dustin,et al.  T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1 , 1989, Nature.

[23]  L. Rohrschneider,et al.  Integrins isolated from Rous sarcoma virus-transformed chicken embryo fibroblasts. , 1989, Oncogene.

[24]  L. Koenderman,et al.  An Improved Method for the Isolation of Eosinophilic Granulocytes From Peripheral Blood of Normal Individuals , 1988, Journal of leukocyte biology.

[25]  D. Golde,et al.  GM-CSF induces human neutrophil IgA-mediated phagocytosis by an IgA Fc receptor activation mechanism , 1988, Nature.

[26]  C. Maliszewski,et al.  The expression of receptors for IgA on human monocytes and calcitriol-treated HL-60 cells. , 1985, Journal of immunology.

[27]  M. Hulett,et al.  Molecular basis of Fc receptor function. , 1994, Advances in immunology.

[28]  I. Dransfield.  Regulation of leukocyte integrin function. , 1991, Chemical immunology.