Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation

Alexandre Semov,Maria J Moreno,Anatoli Onichtchenko,Abedelnasser Abulrob,Marguerite Ball,Irena Ekiel,Grzegorz Pietrzynski,Danica Stanimirovic,Valery Alakhov

doi:10.1074/jbc.m412653200

Abstract

Many advanced tumors overexpress and secrete the S100A4 protein that is known to promote angiogenesis and metastasis development. The mechanisms of this effect and the endothelial receptor for S100A4 are both still unknown. Here we report that extracellular S100A4 interacts with annexin II, an endothelial plasminogen co-receptor. Co-localization and direct binding of S100A4 and annexin II were demonstrated, and the binding site was identified in the N-terminal region of annexin II. S100A4 alone or in a complex with annexin II accelerated tissue plasminogen activator-mediated plasminogen activation in solution and on the endothelial cell surface through interaction of the S100A4 C-terminal lysines with the lysine-binding domains of plasminogen. A synthetic peptide corresponding to the N terminus of annexin II prevented S100A4-induced plasmin formation in the endothelial cell culture. Local plasmin formation induced by circulating S100A4 could contribute to tumor-induced angiogenesis and metastasis formation that makes this protein an attractive target for new anti-cancer and anti-angiogenic therapies.

Highlights

Many advanced tumors overexpress and secrete the S100A4 protein that is known to promote angiogenesis and metastasis development
S100A4 Induces Capillary-like Tube Formation in Primary Human Cerebromicrovascular Endothelial Cells—Angiogenic properties of S100A4 were demonstrated in vitro using human cerebromicrovascular endothelial cells (HCEC) grown in a mixture of basement membrane components, Matrigel
The S100A4-induced capillary-like tube formation was prevented by incubating HCEC with 6-aminocaproic acid (6-ACA) prior to the addition of S100A4 (Fig. 1b)

Summary

Introduction

Many advanced tumors overexpress and secrete the S100A4 protein that is known to promote angiogenesis and metastasis development. The mechanisms of this effect and the endothelial receptor for S100A4 are both still unknown. Local plasmin formation induced by circulating S100A4 could contribute to tumor-induced angiogenesis and metastasis formation that makes this protein an attractive target for new anti-cancer and anti-angiogenic therapies. S100A4 binds to p53 tumor suppressor protein and inhibits its phosphorylation by protein kinase C (PKC) that modulates the expression of p53-regulated genes, such as p21 and bax [16]. The exogenous addition of S100A4 stimulates endothelial cell motility in vitro [24] as well as induces corneal neovascularization [22] and metastasis formation in vivo [27]. The identification of S100A4 endothelial receptor could facilitate the development of anti-angiogenic agents and metastasis inhibitors

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Results

Conclusion