Multipath interaction network of annexin A2: multifaceted regulation and translational perspectives in neurological diseases

Annexin A2 (Anxa2) is a Ca2+-dependent phospholipid-binding protein whose functions are shaped by dynamic membrane association, post-translational regulation, and interactions with diverse molecular partners. Rather than acting as a conventional pathway-specific regulator, Anxa2 appears to operate within a multipath interaction network that links membrane organization, cytoskeletal remodeling, vesicular trafficking, extracellular proteolysis, and cellular stress responses. This Review examines how these interconnected functions contribute to neurological diseases, including Parkinson's disease, Alzheimer's disease, ischemic stroke, traumatic brain injury, and glioma. We critically evaluate evidence connecting Anxa2 with Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/AKT), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Transforming Growth Factor-beta (TGF-β) related signaling and distinguish direct molecular interactions from pathway-dependent or secondary signaling changes. Current evidence suggests that many Anxa2-associated signaling outputs may arise from changes in membrane trafficking, receptor organization, protein handling, and cellular state rather than from direct control of individual signaling cascades. This network-based view also provides a framework for interpreting apparently divergent effects of Anxa2 across neuronal, glial, endothelial, immune, and tumor contexts. From a translational perspective, Anxa2 is therefore a promising but challenging target: its broad physiological functions argue against indiscriminate inhibition and instead favor disease-, cell-, and interaction-specific modulation. Defining the molecular architecture and context-specific operation of Anxa2-centered networks will be essential for determining its value as a biomarker and therapeutic target in neurological disease.