NHERF2 regulatory function in signal transduction pathways and control of gene expression: Implications for cellular homeostasis and breast cancer

Na⁺/H⁺ exchanger regulatory factor 2 (NHERF2) is a nucleocytoplasmic protein initially identified as a regulator of membrane-bound sodium-hydrogen exchanger 3 (NHE3). In the cytoplasm, NHERF2 regulates the activity of G protein-coupled receptors (GPCRs), including beta-2 adrenergic receptor (2β-AR), lysophosphatidic acid receptor 2, and parathyroid hormone type 1 receptor. In the nucleus, NHERF2 acts as a coregulator of transcription factors such as sex-determining region Y protein (SRY), involved in male sex determination, and estrogen receptor alpha (ERα). ERα is a ligand-dependent transcription factor that controls mammary gland growth and differentiation during puberty and pregnancy and plays a major role in the development and progression of breast cancer tumors. Altogether, the regulatory functions of NHERF2 on ion channels, GPCRs, and nuclear transcription factors have a modulatory effect on signal transduction pathways, metabolic homeostasis, cell proliferation and differentiation, neurotransmission, muscle contraction, and renal electrolyte balance. This work highlights NHERF2 functions in the cytoplasm and nucleus and underscores the nuclear mechanisms through which NHERF2 participates in the regulation of gene expression and tumor growth and progression in breast cancer.