NHERF1 is a PDZ scaffold protein that organizes multiprotein signaling complexes at the plasma membrane 1. Its primary function involves linking membrane proteins to the actin cytoskeleton via ezrin/moesin/radixin interactions, regulating surface expression and recycling of receptors including the β2-adrenergic receptor 2. NHERF1 mediates cAMP-dependent signaling in airway smooth muscle and controls ion transporter regulation in intestinal epithelium and renal proximal tubules 23. Specifically, NHERF1 coordinates sodium-hydrogen exchanger (NHE3) and phosphate cotransporter (NPT2A) function through PDZ domain interactions with multiple binding partners 4. NHERF1 exhibits a context-dependent dual role in cancer biology: membrane localization correlates with tumor suppression, while cytoplasmic translocation promotes oncogenic signaling 5. In breast cancer, a novel A190D mutation in the PDZ2 domain enhances nuclear accumulation and increases YAP binding, abolishing tumor suppressive effects 6. In colorectal cancer, elevated NHERF1 expression correlates with metastasis and poor prognosis, functioning downstream of IGF1R signaling to promote cell survival via XIAP/survivin pathways 7. NHERF1 regulates major oncogenic pathways including Wnt-β-catenin, PI3K/AKT, and growth factor receptor signaling 1. These characteristics establish NHERF1 as both a prognostic biomarker and therapeutic target across multiple cancer types.