Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmin formation.
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.
Semov
Alexandre
A
Supratek Pharma Inc., Montreal, Quebec H9S 1A9, Canada.
Moreno
Maria J
MJ
Onichtchenko
Anatoli
A
Abulrob
Abedelnasser
A
Ball
Marguerite
M
Ekiel
Irena
I
Pietrzynski
Grzegorz
G
Stanimirovic
Danica
D
Alakhov
Valery
V
D017306:Annexin A2 / Q000032:analysis / Q000378:metabolism*; D001665:Binding Sites; D002196:Capillaries; D002462:Cell Membrane / Q000737:chemistry; D042783:Endothelial Cells / Q000737:chemistry; D005341:Fibrinolysin / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007163:Immunosorbent Techniques; D007700:Kinetics; D008239:Lysine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008833:Microcirculation / Q000166:cytology; D016296:Mutagenesis; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010958:Plasminogen / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D013329:Structure-Activity Relationship; D013702:Temporal Lobe / Q000098:blood supply; D010959:Tissue Plasminogen Activator / Q000502:physiology
D017306:Annexin A2; D011994:Recombinant Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D008239:Lysine