Peroxynitrite modulates tyrosine-dependent signal transduction pathway of human erythrocyte band 3.
FASEB J
; 11(14): 1281-90, 1997 Dec.
Article
in En
| MEDLINE
| ID: mdl-9409547
ABSTRACT
Peroxynitrite, the product of the reaction between nitric oxide and superoxide anion, is able to nitrate protein tyrosines. If this modification occurs on phosphotyrosine kinase substrates, it can down-regulate cell signaling. We investigated the effects of peroxynitrite on band 3-mediated signal transduction of human erythrocytes. Peroxynitrite treatment induced two different responses. At low concentrations (10-100 microM) it stimulated a metabolic response, leading to 1) a reversible inhibition of phosphotyrosine phosphatase activity, 2) a rise of tyrosine phosphorylation in the 22K cytoplasmic domain of band 3, 3) the release of glyceraldehyde 3-phosphate dehydrogenase from the membrane, and 4) the enhancement of lactate production. At high concentrations (200-1000 microM), peroxynitrite induced 1) cross-linking of membrane proteins, 2) inhibition of band 3 tyrosine phosphorylation, 3) nitration of tyrosines in the 22K cytoplasmic domain of band 3, 4) binding of hemoglobin to the membrane, 5) irreversible inhibition of phosphotyrosine kinase activity, 6) massive methemoglobin production, and 7) irreversible inhibition of lactate production. Our results demonstrate that at concentrations that could conceivably be achieved in vivo (10-100 microM), peroxynitrite behaves like other oxidants, i.e., it stimulates band 3 tyrosine phosphorylation and increases glucose metabolism. Thus, one plausible physiologic effect of peroxynitrite is the up-regulation of signaling through the reversible inhibition of phosphotyrosine phosphatase activity. At high concentrations of peroxynitrite, the tyrosine phosphorylation ceases in parallel with the nitration of band 3 tyrosines, but at these concentrations phosphotyrosine kinase activity and glycolysis are also irreversibly inhibited. Thus, at least in red blood cells, the postulated down-regulation of signaling by peroxynitrite cannot merely be ascribed to the nitration of tyrosine kinase targets.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tyrosine
/
Anion Exchange Protein 1, Erythrocyte
/
Signal Transduction
/
Nitrates
Limits:
Humans
Language:
En
Journal:
FASEB J
Journal subject:
BIOLOGIA
/
FISIOLOGIA
Year:
1997
Document type:
Article
Affiliation country:
Italy