NHERF (
Na+/H+ exchanger regulatory factor or
NHERF-1) and E3KARP (NHE3
kinase A regulatory
protein or
NHERF-2) are structurally related
protein adapters 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 broadening 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 the c-Yes/YAP-65 complex, members of the
phospholipase Cbeta family and the GRK6A
protein kinase to apical surface of polarized epithelial cells where they regulate or respond to membrane signals. While two distinct models have been proposed for
NHERF's role in signal transduction, the common theme is
NHERF's ability to bring together membrane and non-
membrane proteins to regulate cell metabolism and growth.
NHERF overexpression in human breast
cancers and mutations in
NHERF targets, such as CFTR and
merlin, the product of
Neurofibromatosis NF2 tumor suppressor gene, that impair
NHERF binding suggest that aberrant
NHERF function contributes to human disease.