Protein tyrosine phosphatase inhibitors block myeloid signal transduction through the fcγri receptor

Donald L. Durden, Henry Rosen, Bryce R. Michel, Jonathan A. Cooper

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Fc-rcceptor stimulation in certain myeloid cells results in an increase in oxygen consumption termed the respiratory burst. In this report we examine the effects of protein tyrosine phosphatase inhibitors on the Fcγ receptor-induced myeloid respiratory burst. Antiphosphotyrosine immunoblotting of neutrophils stimulated with opsonized oil particles shows that Fc-receptor stimulation is associated with the tyrosine phosphorylation of cellular proteins. Pretreatment of neutrophils for 10 min with vanadate or phenylarsine oxide (PAO), protein tyrosine phosphatase inhibitors, augments tyrosine phosphorylation in response to Fc-receptor stimulation. Vanadate and PAO inhibit the respiratory burst in a dose-dependent fashion, but have no effect on Fcγ receptor-mediated phagocytosis, suggesting that the inhibition of the respiratory burst is not due to a general inhibition of Fcγ-receptor signaling. Neutrophil phagolysosomal membranes were isolated from vanadate-treated and control neutrophils after Fc-receptor stimulation show a reduction in protein tyrosine phosphatase activity and a reduction in the NADPH-dependent oxidase activity and contain greater amounts of phosphotyrosine, relative to control membranes. Vanadate did not inhibit the NADPH-oxidase directly or interfere with the superoxide assay. Vanadate and PAO also inhibited the respiratory burst of interferon-differentiated U937 cells in response to immune complex and FcγRI crosslinking. Pretreatment of U937 cells with PAO completely blocks the serine phosphorylation of the γ subunit, of the FcγR, a response that is associated with FcγRI-receptor activation. The data supports the recent observation that CD45 modulates signal transduction through the FcγRI receptor, suggesting that protein tyrosine phosphatases play a positive modulatory role in the signal relay pathway(s) involving the myeloid FcγRI receptor, resulting in the phosphorylation of the γ subunit and the activation of the NADPH-oxidase complex.

Original languageEnglish (US)
Pages (from-to)150-162
Number of pages13
JournalExperimental Cell Research
Volume211
Issue number1
DOIs
StatePublished - Mar 1994

ASJC Scopus subject areas

  • Cell Biology

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