AMER3 (APC membrane recruitment protein 3) is a positive regulator of canonical Wnt/β-catenin signaling that functions through direct protein interactions with key pathway components. Unlike its family members AMER1 and AMER2 which inhibit Wnt signaling, AMER3 acts as an activator by binding to the armadillo repeat domain of APC and to conductin/axin2 1. The protein localizes to both cytoplasm and nucleus through specific nuclear import/export sequences, lacking the N-terminal membrane localization domain found in other AMER proteins 1. Functionally, AMER3 enhances β-catenin/TCF-dependent reporter gene expression and its knockdown reduces Wnt target gene expression in colorectal cancer cells 1. AMER3 also binds to AMER1, suggesting potential regulatory interactions within the family 1. The gene shows clinical relevance as a potential biomarker in head and neck cancers 2 and esophageal atresia/tracheoesophageal fistula 3. Additionally, AMER3 demonstrates involvement in metabolic regulation, with its methylation mediating associations between environmental exposures and glucose metabolism 45. The AMER gene family originated early in vertebrate evolution through whole genome duplications, with AMER3 representing one of three paralogs with distinct regulatory functions 6.