Fcγ receptor signal transduction in natural killer cells: Coupling to phospholipase C via a G protein-independent, but tyrosine kinase-dependent pathway

A. T. Ting, K. J. Einspahr, R. T. Abraham, P. J. Leibson

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Antibody-dependent cellular cytotoxicity is initiated when low affinity Fc receptors (FcγR type III/CD16) on NK cells bind to sensitized (i.e., antibody coated) target cells. FcγR cross-linkage induces the activation of phospholipase C (PLC), which hydrolyses membrane phosphoinositides, generating inositol-1,4,5-trisphosphate and sn-1,2-diacylglycerol as second messengers. However, the mechanism that couples FcγR stimulation to PLC activation remains unknown. In this study, we investigated whether the FcγR is coupled to PLC via a guanine nucleotide-binding (G) protein or an alternative pathway. Stimulation of electropermeabilized human NK cells with GTPγS induced inositol phosphate (IP) release, indicating the presence of a G protein-linked PLC activity in these cells. However, stimulation with both anti-FcγR mAb and GTPγS provoked additive rather than synergistic increases in IP formation. Furthermore, exogenous GDP strongly inhibited GTPγS-stimulated IP release, but failed to inhibit the response to anti-FcγR mAb stimulation. These results suggested GTPγS and anti-FcγR mAb activated PLC through distinct regulatory mechanisms, and that FcγR was not linked to PLC via a G protein. Hence, an alternative transduction mechanism for FcγR-PLC coupling was considered. Antibody-mediated FcγR cross-linkage was shown to rapidly stimulate tyrosine phosphorylation of multiple proteins in NK cells. Pretreatment with the tyrosine kinase inhibitor, herbimycin A, inhibited these phosphorylation events and disrupted the coupling between FcγR ligation and PLC activation. These observations suggest that FcγR in NK cell is coupled to PLC via a G protein-independent, but tyrosine kinase-dependent pathway.

Original languageEnglish (US)
Pages (from-to)3122-3127
Number of pages6
JournalJournal of Immunology
Volume147
Issue number9
StatePublished - 1991

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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