The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function

Xiaoli Li, Julie G. Baskin, Erin K. Mangan, Kaihong Su, Andrew W. Gibson, Chuanyi Ji, Jeffrey C. Edberg, Robert P. Kimberly

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Ligand specificity characterizes receptors for Abs and many other immune receptors, but the common use of the FcR γ-chain as their signaling subunit challenges the concept that these receptors are functionally distinct. We hypothesized that elements for specificity might be determined by the unique cytoplasmic domain (CY) sequences of the ligand-binding α-chains of γ-chain-associated receptors. Among Fcγ receptors, a protein kinase C (PKC) phosphorylation consensus motif [RSSTR], identified within the FcγRIIIa (CD16A) CY by in silico analysis, is specifically phosphorylated by PKCs, unlike other FcRs. Phosphorylated CD16A mediates a more robust calcium flux, tyrosine phosphorylation of Syk, and proinflammatory cytokine production, whereas non-phosphorylatable CD16A is more effective at activation of the Gab2/PI3K pathway, leading to enhanced degranulation. S100A4, a specific protein-binding partner for CD16A-CY newly identified by yeast two-hybrid analysis, inhibits phosphorylation of CD16A-CY by PKC in vitro, and reduction of S100A4 levels in vivo enhances receptor phosphorylation upon cross-linking. Taken together, PKC-mediated phosphorylation of CD16A modulates distinct signaling pathways engaged by the receptor. Calcium-activated binding of S100A4 to CD16A, promoted by the initial calcium flux, attenuates the phosphorylation of CY, and, acting as a molecular switch, may both serve as a negative feedback on cytokine production pathways during sustained receptor engagement and favor a shift to degranulation, consistent with the importance of granule release following conjugate formation between CD16A+ effector cells and target cells. This switch mechanism points to new therapeutic targets and provides a framework for understanding novel receptor polymorphisms.

Original languageEnglish (US)
Pages (from-to)4284-4294
Number of pages11
JournalJournal of Immunology
Volume189
Issue number9
DOIs
StatePublished - Nov 1 2012

Fingerprint

Phosphorylation
Protein Kinase C
Calcium
Cytokines
Ligands
Fc Receptors
Phosphatidylinositol 3-Kinases
Protein Binding
Computer Simulation
Tyrosine
Yeasts
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Li, X., Baskin, J. G., Mangan, E. K., Su, K., Gibson, A. W., Ji, C., ... Kimberly, R. P. (2012). The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function. Journal of Immunology, 189(9), 4284-4294. https://doi.org/10.4049/jimmunol.1200704

The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function. / Li, Xiaoli; Baskin, Julie G.; Mangan, Erin K.; Su, Kaihong; Gibson, Andrew W.; Ji, Chuanyi; Edberg, Jeffrey C.; Kimberly, Robert P.

In: Journal of Immunology, Vol. 189, No. 9, 01.11.2012, p. 4284-4294.

Research output: Contribution to journalArticle

Li, X, Baskin, JG, Mangan, EK, Su, K, Gibson, AW, Ji, C, Edberg, JC & Kimberly, RP 2012, 'The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function', Journal of Immunology, vol. 189, no. 9, pp. 4284-4294. https://doi.org/10.4049/jimmunol.1200704
Li, Xiaoli ; Baskin, Julie G. ; Mangan, Erin K. ; Su, Kaihong ; Gibson, Andrew W. ; Ji, Chuanyi ; Edberg, Jeffrey C. ; Kimberly, Robert P. / The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function. In: Journal of Immunology. 2012 ; Vol. 189, No. 9. pp. 4284-4294.
@article{ed9c178ae8ab482cb6546fdc19cd2455,
title = "The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function",
abstract = "Ligand specificity characterizes receptors for Abs and many other immune receptors, but the common use of the FcR γ-chain as their signaling subunit challenges the concept that these receptors are functionally distinct. We hypothesized that elements for specificity might be determined by the unique cytoplasmic domain (CY) sequences of the ligand-binding α-chains of γ-chain-associated receptors. Among Fcγ receptors, a protein kinase C (PKC) phosphorylation consensus motif [RSSTR], identified within the FcγRIIIa (CD16A) CY by in silico analysis, is specifically phosphorylated by PKCs, unlike other FcRs. Phosphorylated CD16A mediates a more robust calcium flux, tyrosine phosphorylation of Syk, and proinflammatory cytokine production, whereas non-phosphorylatable CD16A is more effective at activation of the Gab2/PI3K pathway, leading to enhanced degranulation. S100A4, a specific protein-binding partner for CD16A-CY newly identified by yeast two-hybrid analysis, inhibits phosphorylation of CD16A-CY by PKC in vitro, and reduction of S100A4 levels in vivo enhances receptor phosphorylation upon cross-linking. Taken together, PKC-mediated phosphorylation of CD16A modulates distinct signaling pathways engaged by the receptor. Calcium-activated binding of S100A4 to CD16A, promoted by the initial calcium flux, attenuates the phosphorylation of CY, and, acting as a molecular switch, may both serve as a negative feedback on cytokine production pathways during sustained receptor engagement and favor a shift to degranulation, consistent with the importance of granule release following conjugate formation between CD16A+ effector cells and target cells. This switch mechanism points to new therapeutic targets and provides a framework for understanding novel receptor polymorphisms.",
author = "Xiaoli Li and Baskin, {Julie G.} and Mangan, {Erin K.} and Kaihong Su and Gibson, {Andrew W.} and Chuanyi Ji and Edberg, {Jeffrey C.} and Kimberly, {Robert P.}",
year = "2012",
month = "11",
day = "1",
doi = "10.4049/jimmunol.1200704",
language = "English (US)",
volume = "189",
pages = "4284--4294",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "9",

}

TY - JOUR

T1 - The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function

AU - Li, Xiaoli

AU - Baskin, Julie G.

AU - Mangan, Erin K.

AU - Su, Kaihong

AU - Gibson, Andrew W.

AU - Ji, Chuanyi

AU - Edberg, Jeffrey C.

AU - Kimberly, Robert P.

PY - 2012/11/1

Y1 - 2012/11/1

N2 - Ligand specificity characterizes receptors for Abs and many other immune receptors, but the common use of the FcR γ-chain as their signaling subunit challenges the concept that these receptors are functionally distinct. We hypothesized that elements for specificity might be determined by the unique cytoplasmic domain (CY) sequences of the ligand-binding α-chains of γ-chain-associated receptors. Among Fcγ receptors, a protein kinase C (PKC) phosphorylation consensus motif [RSSTR], identified within the FcγRIIIa (CD16A) CY by in silico analysis, is specifically phosphorylated by PKCs, unlike other FcRs. Phosphorylated CD16A mediates a more robust calcium flux, tyrosine phosphorylation of Syk, and proinflammatory cytokine production, whereas non-phosphorylatable CD16A is more effective at activation of the Gab2/PI3K pathway, leading to enhanced degranulation. S100A4, a specific protein-binding partner for CD16A-CY newly identified by yeast two-hybrid analysis, inhibits phosphorylation of CD16A-CY by PKC in vitro, and reduction of S100A4 levels in vivo enhances receptor phosphorylation upon cross-linking. Taken together, PKC-mediated phosphorylation of CD16A modulates distinct signaling pathways engaged by the receptor. Calcium-activated binding of S100A4 to CD16A, promoted by the initial calcium flux, attenuates the phosphorylation of CY, and, acting as a molecular switch, may both serve as a negative feedback on cytokine production pathways during sustained receptor engagement and favor a shift to degranulation, consistent with the importance of granule release following conjugate formation between CD16A+ effector cells and target cells. This switch mechanism points to new therapeutic targets and provides a framework for understanding novel receptor polymorphisms.

AB - Ligand specificity characterizes receptors for Abs and many other immune receptors, but the common use of the FcR γ-chain as their signaling subunit challenges the concept that these receptors are functionally distinct. We hypothesized that elements for specificity might be determined by the unique cytoplasmic domain (CY) sequences of the ligand-binding α-chains of γ-chain-associated receptors. Among Fcγ receptors, a protein kinase C (PKC) phosphorylation consensus motif [RSSTR], identified within the FcγRIIIa (CD16A) CY by in silico analysis, is specifically phosphorylated by PKCs, unlike other FcRs. Phosphorylated CD16A mediates a more robust calcium flux, tyrosine phosphorylation of Syk, and proinflammatory cytokine production, whereas non-phosphorylatable CD16A is more effective at activation of the Gab2/PI3K pathway, leading to enhanced degranulation. S100A4, a specific protein-binding partner for CD16A-CY newly identified by yeast two-hybrid analysis, inhibits phosphorylation of CD16A-CY by PKC in vitro, and reduction of S100A4 levels in vivo enhances receptor phosphorylation upon cross-linking. Taken together, PKC-mediated phosphorylation of CD16A modulates distinct signaling pathways engaged by the receptor. Calcium-activated binding of S100A4 to CD16A, promoted by the initial calcium flux, attenuates the phosphorylation of CY, and, acting as a molecular switch, may both serve as a negative feedback on cytokine production pathways during sustained receptor engagement and favor a shift to degranulation, consistent with the importance of granule release following conjugate formation between CD16A+ effector cells and target cells. This switch mechanism points to new therapeutic targets and provides a framework for understanding novel receptor polymorphisms.

UR - http://www.scopus.com/inward/record.url?scp=84867911797&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867911797&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1200704

DO - 10.4049/jimmunol.1200704

M3 - Article

C2 - 23024279

AN - SCOPUS:84867911797

VL - 189

SP - 4284

EP - 4294

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 9

ER -