A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange

Activation of the ubiquitously expressed Na-H exchanger, NHE1, results in an increased efflux of intracellular H+, The increase in intracellular pH associated with this H+ efflux may contribute to regulating cell proliferation, differentiation, and neoplastic transformation. Although NHE1 activity is stimulated by growth factors and hormones acting through multiple GTPase-mediated pathways, little is known about how the exchanger is directly regulated. Using expression library screening, we identified a novel protein that specifically binds to NHE1 at a site that is critical for growth factor stimulation of exchange activity, This protein is homologous to calcineurin B and calmodulin and is designated CHP for calcineurin B homologous protein, Like NHE1, CHP is widely expressed in human tissues, Transient overexpression of CHP inhibits serum- and GTPase stimulated NHE1 activity. CHP is a phosphoprotein and expression of constitutively activated GTPases decreases CHP phosphorylation, The phosphorylation state of CHP may therefore be an important signal controlling mitogenic regulation of NHE1.