Annexin A2 System in Human Biology: Cell Surface and Beyond

Abstract

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 plasma membrane, 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, A2 maintains 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.

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

“…For example, in prostate cancer cells, activated α 2 M might bind to GRP78, which becomes externalized and associated with the cell surface (Misra et al, 2011). Similarly, tPA might bind to cell surface annexin A2, eliciting diverse responses in endothelial cells and other cell types (Luo and Hajjar, 2013). The ability of α 2 M*, EItPA and MMP9 to activate ERK1/2 similarly and the ability of two separate LRP1 signaling antagonists (RAP and lactoferrin) to block these responses confirms the essential role of LRP1.…”

Annexins – insights from knockout mice

“…Different models of AnxA2/p11-mediated plasminogen activation have been proposed. We recommend several reviews that have extensively discussed the formation, structural organization, translocation and mode of action of the extracellular AnxA2/p11 complex (Flood and Hajjar, 2011;Grieve et al, 2012;Hedhli et al, 2012;Bharadwaj et al, 2013;Luo and Hajjar, 2013;Bydoun and Waisman, 2014).…”

“…The consequences of high or low plasma levels of AnxA2/p11 in several human diseases linked to vascular homeostasis and angiogenesis have been discussed (Flood and Hajjar, 2011;Hedhli et al, 2012;Bharadwaj et al, 2013;Luo and Hajjar, 2013;Bydoun and Waisman, 2014). For instance, diet-induced hyperhomocysteinemia, which is implicated in thrombotic and atherosclerotic disease, shows fibrin accumulation and defects in neoangiogenesis resembling those observed in the AnxA2 -/-mice ).…”

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“…This issue begins with reviews on the major components of the P-P system. These include a review by Miles and Parmer on recently discovered plasminogen receptors, 4 an update on a role for the canonical plasminogen receptor, annexin A2, in diseases, 5 followed by a molecular view of the uPA receptor (uPAR) by Ferraris and Sidenius. 6 Another member of the P-P system that has a versatile role in biology and the pathogenesis of many diseases is PAI-1 and its implication on various processes is expanding almost on a daily basis.…”