A PDZ-interacting domain in CFTR is an apical membrane polarization signal

Polarization of the cystic fibrosis transmembrane conductance regulator (CF TR), a cAMP-activated chloride channel, to the apical plasma membrane of ep ithelial cells is critical for vectorial transport of chloride in a variety of epithelia, including the airway, pancreas, intestine, and kidney. Howev er, the motifs that localize CFTR to the apical membrane are unknown. We re port that the last 3 amino acids in the COOH-terminus of CFTR (T-R-L) compr ise a PDZ-interacting domain that is required for the polarization of CFTR to the apical plasma membrane in human airway and kidney epithelial cells. In addition, the CFTR mutant, S1455X, which lacks the 26 COOH-terminal amin o acids, including the PDZ-interacting domain, is mispolarized to the later al membrane. We also demonstrate that CFTR binds to ezrin-radixin-moesin-bi nding phosphoprotein 50 (EBP50), an apical membrane PDZ domain-containing p rotein. We propose that COOH-terminal deletions of CFTR, which represent ab out 10% of CFTR mutations, result in defective vectorial chloride transport , partly by altering the polarized distribution of CFTR in epithelial cells . Moreover, our data demonstrate that PDZ-interacting domains and PDZ domai n-containing proteins play a key role in the apical polarization of ion cha nnels in epithelial cells.