Expanding the role of NHERF, a PDZ-domain containing protein adapter, to growth regulation

NHERF (Na+/H+ exchanger regulatory factor or NHERF-1) and E3KARP (NHE3 kina se A regulatory protein or NHERF-2) are structurally related protein adapte rs that are highly expressed in epithelial tissues. NHERF proteins contain two tandem PDZ domains and a C-terminal sequence that binds several members of the ERM (ezrin-radixin-moesin) family of membrane-cytoskeletal adapters . Although identified as a regulator of NHE3, recent evidence points to a b roadening role for NHERF in the function, localization and/or turnover of G -protein coupled receptors, platelet-derived growth factor receptor and ion transporters such as CFTR, Na/Pi cotransporter, Na/HCO3 cotransporter and Trp (calcium) channels. NHERF also recruits non-membrane proteins such as t he c-Yes/YAP-65 complex, members of the phospholipase Cp family and the GRK 6A protein kinase to apical surface of polarized epithelial cells where the y regulate or respond to membrane signals. While two distinct models have b een proposed for NHERF's role in signal transduction, the common theme is N HERF's ability to bring together membrane and non-membrane proteins to regu late cell metabolism and growth. NHERF overexpression in human breast cance rs and mutations in NHERF targets, such as CFTR and merlin, the product of Neurofibromatosis NF2 tumor suppressor gene, that impair NHERF binding sugg est that aberrant NHERF function contributes to human disease.