The annexin A2/S100A10 system in health and disease: emerging paradigms.

Nadia Hedhli,Haiyan Zhai,Rosemary Kraemer,Laura Santambrogio,Gabriela Cesarman-Maus,Katherine A Hajjar,Bihui Huang,Domenick J Falcone,Stella E Tsirka

doi:10.1155/2012/406273

Abstract

Since its discovery as a src kinase substrate more than three decades ago, appreciation for the physiologic functions of annexin A2 and its associated proteins has increased dramatically. With its binding partner S100A10 (p11), A2 forms a cell surface complex that regulates generation of the primary fibrinolytic protease, plasmin, and is dynamically regulated in settings of hemostasis and thrombosis. In addition, the complex is transcriptionally upregulated in hypoxia and promotes pathologic neoangiogenesis in the tissues such as the retina. Dysregulation of both A2 and p11 has been reported in examples of rodent and human cancer. Intracellularly, A2 plays a critical role in endosomal repair in postarthroplastic osteolysis, and intracellular p11 regulates serotonin receptor activity in psychiatric mood disorders. In human studies, the A2 system contributes to the coagulopathy of acute promyelocytic leukemia, and is a target of high-titer autoantibodies in patients with antiphospholipid syndrome, cerebral thrombosis, and possibly preeclampsia. Polymorphisms in the human ANXA2 gene have been associated with stroke and avascular osteonecrosis of bone, two severe complications of sickle cell disease. Together, these new findings suggest that manipulation of the annexin A2/S100A10 system may offer promising new avenues for treatment of a spectrum of human disorders.

Highlights

The A2 system contributes to the coagulopathy of acute promyelocytic leukemia, and is a target of high-titer autoantibodies in patients with antiphospholipid syndrome, cerebral thrombosis, and possibly preeclampsia
Microvascular endothelial cells isolated from AnxA2−/− mice, lack the ability to support tissue plasminogen activator (tPA)-dependent plasmin generation in vitro, and arterial injury in vivo leads to an increased rate and severity of vascular occlusion in the AnxA2−/− mouse
When wild type mice were subjected to diet-induced hyperhomocysteinemia, fibrin accumulated in multiple tissues (Figure 1(d)), and extracted A2 failed to support tPA binding or tPA-dependent plasmin generation, revealing that HC-induced blockade of the cell surface A2 pathway can occur in vivo

Summary

Introduction

With its binding partner S100A10 (p11), A2 forms a cell surface complex that regulates generation of the primary fibrinolytic protease, plasmin, and is dynamically regulated in settings of hemostasis and thrombosis. The A2 system contributes to the coagulopathy of acute promyelocytic leukemia, and is a target of high-titer autoantibodies in patients with antiphospholipid syndrome, cerebral thrombosis, and possibly preeclampsia. TPA-dependent plasminogen activation is dramatically accelerated in the presence of fibrin, and to a lesser extent by cell surface fibrinolytic receptors.

Results

Conclusion