Calcineurin B Homologous Protein Regulation of the Sodium Hydrogen Exchanger Isoform 1 More than Competition, the Need for a CHP-Specific Therapy

The development of pathophysiologies including fibrosis and cancers involve the establishment of a tissue microenvironment characterized by hypoxia and low serum conditions. NHE1 directly influences cell proliferation, extracellular matrix composition, and cell migration in multiple disease states. Calcineurin homologous protein isoforms 1 and 2 (CHP1 & 2) are calcium-binding proteins whose function is not well understood. CHP1 is crucial for NHE1 membrane processing and basal transport activity. Additionally, CHP1 is involved in the regulation of gene expression. In contrast, CHP2 expression is limited to a small range of cells types its primary function is ascribed to the regulation of NHE1. Preferential binding of CHP2 to NHE1 under the tumor microenvironment supports cell survival by first activating the exchanger through the CHP2-NHE1 interaction and by freeing CHP1 to the nucleus where it also supports cell survival. The affinity of CHP2 is three-fold greater than CHP1, but endogenous CHP concentrations indicates that competition alone cannot explain the role of CHP2. Modelling of CHP binding identified two distinct approaches to establishing the CHP-NHE1 interaction; CHP1 binds in a two state-mechanism and CHP2 bound NHE1 in a one state-mechanism. Additional analysis of predicted and published phosphorylation sites of the CHPs suggest that phosphorylation can support a CHP specific interaction with NHE1. Together these data and models highlight a means to identify possible therapies that target CHP2 but not CHP1 to defeat cell survival in several disease states.