Annexin A2 System in Human Biology: Cell Surface and Beyond

Annexin A2 (A2) is a multicompartmental, multifunctional protein that orchestrates a growing spectrum of biologic processes. At the endothelial cell surface, A2 and S100A10 (p11) form a heterotetramer, which accelerates tissue plasminogen activator- dependent activation of the fibrinolytic protease, plasmin. In antiphospholipid syndrome, anti- A2 antibodies are associated with clinical thrombosis, whereas overexpression of A2 in acute promyelocytic leukemia promotes hyperfibrinolytic bleeding. A2 is upregulated in hypoxia, and mice deficient in A2 are resistant to oxygen- induced retinal neovascularization, suggesting a role for A2 in human retinal vascular proliferation. In solid malignancies, the (A2.p11)(2) tetramer may promote cancer cell invasion, whereas in multiple myeloma A2 enables malignant plasmacyte growth and predicts prognosis. In the central nervous system, the p11 enables membrane insertion of serotonin receptors that govern mood. In the peripheral nervous system, p11 directs sodium channels to the plasmamembrane, enabling pain perception. In cerebral cortex neurons, A2 stabilizes the microtubule- associated tau protein, which, when mutated, is associated with frontotemporal dementia. In inflammatory dendritic cells, A2maintains late endosomal/ lysosomal membrane integrity, thus modulating inflammasome activation and cytokine secretion in a model of aseptic arthritis. Together, these findings suggest an emerging, multifaceted role for A2 in human health and disease.