AP2-associated protein kinase 1

AP2-associated protein kinase 1 (AAK1) is a serine/threonine kinase that regulates clathrin-mediated endocytosis by phosphorylating the AP2M1 subunit of adaptor protein complex 2 (AP-2), thereby promoting high-affinity cargo binding during the initial stages of endocytosis (UniProt: Q2M2I8). The protein also phosphorylates NUMB, regulating its localization to endosomes, and modulates NOTCH1 signaling through endosomal trafficking. Beyond its core endocytic function, AAK1 participates in viral lifecycle regulation, including hepatitis C virus entry.

AAK1 is widely expressed and functions as a key regulator of vesicular trafficking processes. The protein's role in endocytosis and intracellular protein localization positions it within pathways critical for neuronal membrane homeostasis and signaling (UniProt: Q2M2I8).

In Alzheimer's disease, AAK1 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.74 across subcellular fractions (Chaparral AD proteomics). This downregulation may impair endocytic capacity and trafficking of membrane proteins implicated in neuronal dysfunction, suggesting a potential contribution to AD pathophysiology through reduced vesicular transport efficiency.