AP2M1 is the μ-subunit of adaptor protein complex 2 (AP-2), a core component of clathrin-mediated endocytosis machinery 1. AP2M1 functions as a cargo adaptor that bridges clathrin coats to membrane components and recognizes tyrosine-based endocytosis motifs (Y-X-X-Φ) on transmembrane proteins 2. Upon membrane association, phosphorylation of AP2M1 at Thr-156 by AAK1 kinase enables cargo binding 3. AP2M1 mediates internalization of diverse cargo including transferrin receptors for iron uptake, claudin-2 for barrier function, and notch receptors in hematopoietic cells 425. In normal physiology, AP2M1 enables receptor-mediated endocytosis and synaptic vesicle recycling. Dysregulation causes neurodevelopmental disease: AP2M1 haploinsufficiency from 3q27 deletions causes microcephaly, intellectual disability, seizures, and growth restriction 6. Loss-of-function variants produce severe epilepsy 6. Conversely, AP2M1 overexpression drives multiple malignancies: elevated levels enhance chemoresistance in acute myeloid leukemia through Notch1 pathway activation 51, promote proliferation in salivary gland carcinomas 7, and predict poor Dupilumab response in atopic dermatitis 8. AP2M1 represents both a critical endocytic regulator and an emerging therapeutic target across neurological and oncological diseases.