Nucleoside diphosphate kinase - a component of the [Na+]- and [Cl-]-sensitive phosphorylation cascade in human and murine airway epithelium

We have shown that proteins within apically enriched fractions of human nas al respiratory epithelium vary their phosphohistidine content with ambient [CF] and other anion concentrations. This membrane-delimited phosphorylatio n cascade includes a multifunctional protein histidine kinase - nucleoside diphosphate kinase (NDPK). NDPK is itself a cascade component in both human and ovine airway, the self-phosphorylation of which is inhibited selective ly by [Na+] in the presence of ATP (but not GTP). These findings led us to propose the existence of a dual anion-/cation-controlled phosphorylation-ba sed "sensor" bound to the apical membrane. The present study showed that th is cascade uses ATP to phosphorylate a group of proteins above 45 kDa (p45- group, identities unknown). Additionally, the Cl- dependence of ATP (but no t GTP) phosphorylation is conditional on phosphatase activity and that inte ractions exist between the ATP- and GTP-phosphorylated components of the ca scade under Cl--free conditions. As a prelude to studies in cystic fibrosis (CF) mice, we showed in the present study that NDPK is present and functio nally active in normal murine airway. Since NDPK is essential for UTP synth esis and regulates fetal gut development, G proteins, K+ channels, neutroph il-mediated inflammation and pancreatic secretion, the presence of ion-regu lated NDPK protein in mouse airway epithelium might aid understanding of th e pathogenesis of CF.