NHERF2 (NHERF family PDZ scaffold protein 2) is a multifunctional scaffold protein that operates in both cytoplasmic and nuclear compartments to regulate diverse cellular processes. In the cytoplasm, NHERF2 serves as a crucial scaffold linking plasma membrane proteins to the actin cytoskeleton through interactions with ezrin/radixin/moesin (ERM) family proteins 1. The protein contains an ERM-binding domain (EBD) and an upstream ERM-binding regulatory sequence (EBRS) that facilitate ezrin binding and proper apical membrane localization 2. NHERF2 regulates multiple membrane proteins including NHE3 sodium-hydrogen exchanger, where it is necessary for cAMP-mediated phosphorylation and inhibition 3, and forms complexes with CFTR and LPA2 receptor in airway and gut epithelia 4. The protein also modulates G protein-coupled receptor signaling, including beta-2 adrenergic and parathyroid hormone receptors 5. In the nucleus, NHERF2 functions as a transcriptional coregulator, notably for estrogen receptor alpha (ERα) in breast cancer progression 5. Clinical significance includes its role in HPV16-driven oropharyngeal cancers, where HPV16 E6 oncoprotein targets NHERF2 for proteasomal degradation, contributing to oncogenesis 6. NHERF2's diverse regulatory functions impact signal transduction, metabolic homeostasis, and cellular differentiation.