Lin X, Barber D L
Department of Stomatology, University of California, San Francisco 94143, USA.
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12631-6. doi: 10.1073/pnas.93.22.12631.
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 GTP-ase-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.
广泛表达的钠氢交换体NHE1的激活会导致细胞内H⁺外流增加。与这种H⁺外流相关的细胞内pH升高可能有助于调节细胞增殖、分化和肿瘤转化。尽管NHE1活性受到通过多种GTP酶介导途径起作用的生长因子和激素的刺激，但对于该交换体如何直接被调节却知之甚少。通过表达文库筛选，我们鉴定出一种新型蛋白质，它在对生长因子刺激交换活性至关重要的位点特异性结合NHE1。这种蛋白质与钙调神经磷酸酶B和钙调蛋白同源，被命名为CHP，即钙调神经磷酸酶B同源蛋白。与NHE1一样，CHP在人体组织中广泛表达。CHP的瞬时过表达会抑制血清和GTP酶刺激的NHE1活性。CHP是一种磷蛋白，组成型激活的GTP酶的表达会降低CHP的磷酸化水平。因此，CHP的磷酸化状态可能是控制NHE1促有丝分裂调节的重要信号。
